MANF serves as a novel hepatocyte factor to promote liver regeneration after 2/3 partial hepatectomy via doubly targeting Wnt/ß-catenin signaling.

Liver regeneration is an intricate pathophysiological process that has been a subject of great interest to the scientific community for many years. The capacity of liver regeneration is very critical for patients with liver diseases. Therefore, exploring the mechanisms of liver regeneration and finding good ways to improve it are very meaningful. Mesencephalic astrocyte-derived neurotrophic factor (MANF), a member of newly identified neurotrophic factors (NTFs) family, extensively expresses in the liver and has demonstrated cytoprotective effects during ER stress and inflammation. However, the role of MANF in liver regeneration remains unclear. Here, we used hepatocyte-specific MANF knockout (MANFHep-/-) mice to investigate the role of MANF in liver regeneration after 2/3 partial hepatectomy (PH). Our results showed that MANF expression was up-regulated in a time-dependent manner, and the peak level of mRNA and protein appeared at 24 h and 36 h after 2/3 PH, respectively. Notably, MANF knockout delayed hepatocyte proliferation, and the peak proliferation period was delayed by 24 h. Mechanistically, our in vitro results showed that MANF physically interacts with LRP5 and ß-catenin, two essential components of Wnt/ß-catenin pathway. Specifically, as a cofactor, MANF binds to the extracellular segment of LRP5 to activate Wnt/ß-catenin signaling. On the other hand, MANF interacts with ß-catenin to stabilize cytosolic ß-catenin level and promote its nuclear translocation, which further enhance the Wnt/ß-catenin signaling. We also found that MANF knockout does not affect the c-Met/ß-catenin complex after 2/3 PH. In summary, our study confirms that MANF may serve as a novel hepatocyte factor that is closely linked to the activation of the Wnt/ß-catenin pathway via intracellular and extracellular targets.

Spatial Steerability of GANs via Self-Supervision from Discriminator.

Generative models make huge progress to the photorealistic image synthesis in recent years. To enable human to steer the image generation process and customize the output, many works explore the interpretable dimensions of the latent space in GANs. Existing methods edit the attributes of the output image such as orientation or color scheme by varying the latent code along certain directions. However, these methods usually require additional human annotations for each pretrained model, and they mostly focus on editing global attributes. In this work, we propose a self-supervised approach to improve the spatial steerability of GANs without searching for steerable directions in the latent space or requiring extra annotations. Specifically, we design randomly sampled Gaussian heatmaps to be encoded into the intermediate layers of generative models as spatial inductive bias. Along with training the GAN model from scratch, these heatmaps are being aligned with the emerging attention of the GAN's discriminator in a self-supervised learning manner. During inference, users can interact with the spatial heatmaps in an intuitive manner, enabling them to edit the output image by adjusting the scene layout, moving, or removing objects. Moreover, we incorporate DragGAN into our framework, which facilitates fine-grained manipulation within a reasonable time and supports a coarse-to-fine editing process. Extensive experiments show that the proposed method not only enables spatial editing over human faces, animal faces, outdoor scenes, and complicated multi-object indoor scenes but also brings improvement in synthesis quality. Code, models, and demo video are available at https://genforce.github.io/SpatialGAN/.

Genome-Wide Methylation Analysis Reveals a KCNK3-Prominent Causal Cascade on Hypertension.

BACKGROUND: Despite advances in understanding hypertension's genetic structure, how noncoding genetic variants influence it remains unclear. Studying their interaction with DNA methylation is crucial to deciphering this complex disease's genetic mechanisms. METHODS: We investigated the genetic and epigenetic interplay in hypertension using whole-genome bisulfite sequencing. Methylation profiling in 918 males revealed allele-specific methylation and methylation quantitative trait loci. We engineered rs1275988T/C mutant mice using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9), bred them for homozygosity, and subjected them to a high-salt diet. Telemetry captured their cardiovascular metrics. Protein-DNA interactions were elucidated using DNA pull-downs, mass spectrometry, and Western blots. A wire myograph assessed vascular function, and analysis of the Kcnk3 gene methylation highlighted the mutation's role in hypertension. RESULTS: We discovered that DNA methylation-associated genetic effects, especially in non-cytosine-phosphate-guanine (non-CpG) island and noncoding distal regulatory regions, significantly contribute to hypertension predisposition. We identified distinct methylation quantitative trait locus patterns in the hypertensive population and observed that the onset of hypertension is influenced by the transmission of genetic effects through the demethylation process. By evidence-driven prioritization and in vivo experiments, we unearthed rs1275988 in a cell type-specific enhancer as a notable hypertension causal variant, intensifying hypertension through the modulation of local DNA methylation and consequential alterations in Kcnk3 gene expression and vascular remodeling. When exposed to a high-salt diet, mice with the rs1275988C/C genotype exhibited exacerbated hypertension and significant vascular remodeling, underscored by increased aortic wall thickness. The C allele of rs1275988 was associated with elevated DNA methylation levels, driving down the expression of the Kcnk3 gene by attenuating Nr2f2 (nuclear receptor subfamily 2 group F member 2) binding at the enhancer locus. CONCLUSIONS: Our research reveals new insights into the complex interplay between genetic variations and DNA methylation in hypertension. We underscore hypomethylation's potential in hypertension onset and identify rs1275988 as a causal variant in vascular remodeling. This work advances our understanding of hypertension's molecular mechanisms and encourages personalized health care strategies.

Study on the evaluation method of cigarette astringency in the simulated oral environment.

Cigarettes with pronounced astringency can diminish consumers' enjoyment. However, due to the complex composition of cigarettes, quantifying astringency intensity accurately has been challenging. To address this, research was conducted to develop a method for assessing astringency intensity in a simulated oral environment. The astringency intensity of four cigarette brands was determined using the standard sensory evaluation method. The mainstream smoke absorbing solution (MS) was prepared by simulating the cigarette smoking process, and its physicochemical properties (such as total phenol content and pH levels) were analyzed. The lubrication properties of the five solutions were tested using the MFT-5000 wear tester, and factors influencing cigarette astringency were examined. The findings showed that total phenol content and pH of MS were positively and negatively correlated with astringency intensity, respectively. Particularly, the lubrication properties of MS were significantly correlated with astringency intensity, and the correlation coefficient was affected by load and speed during testing. The study concluded that coefficient of friction was a more reliable measure for assessing the extent of astringency in cigarettes than the total phenol content and pH of MS, offering new insights into astringency evaluation and development of high-grade cigarettes.

In-Domain GAN Inversion for Faithful Reconstruction and Editability.

Generative Adversarial Networks (GANs) have significantly advanced image synthesis through mapping randomly sampled latent codes to high-fidelity synthesized images. However, applying well-trained GANs to real image editing remains challenging. A common solution is to find an approximate latent code that can adequately recover the input image to edit, which is also known as GAN inversion. To invert a GAN model, prior works typically focus on reconstructing the target image at the pixel level, yet few studies are conducted on whether the inverted result can well support manipulation at the semantic level. This work fills in this gap by proposing in-domain GAN inversion, which consists of a domain-guided encoder and a domain-regularized optimizer, to regularize the inverted code in the native latent space of the pre-trained GAN model. In this way, we manage to sufficiently reuse the knowledge learned by GANs for image reconstruction, facilitating a wide range of editing applications without any retraining. We further make comprehensive analyses on the effects of the encoder structure, the starting inversion point, as well as the inversion parameter space, and observe the trade-off between the reconstruction quality and the editing property. Such a trade-off sheds light on how a GAN model represents an image with various semantics encoded in the learned latent distribution.

Potential of novel iron 1,3,5-benzene tricarboxylate loaded on biochar to reduce ammonia and nitrous oxide emissions and its associated biological mechanism during composting.

In this study, a novel iron 1,3,5-benzene tricarboxylate loaded on biochar (BC-FeBTC) was developed and applied to kitchen waste composting. The results demonstrated that the emissions of NH3 and N2O were significantly reduced by 57.2% and 37.8%, respectively, compared with those in control group (CK). Microbiological analysis indicated that BC-FeBTC addition altered the diversity and abundance of community structure as well as key functional genes. The nitrification genes of ammonia-oxidizing bacteria were enhanced, thereby promoting nitrification and reducing the emission of NH3. The typical denitrifying bacterium, Pseudomonas, and critical functional genes (nirS, nirK, and nosZ) were significantly inhibited, contributing to reduced N2O emissions. Network analysis further revealed the important influence of BC-FeBTC in nitrogen transformation driven by functional microbes. These findings offer crucial scientific foundation and guidance for the application of novel materials aimed at mitigating nitrogen loss and environmental pollution during composting.

Study of the variation law of the airflow resistance and related physical parameters of the pile throughout compost process with cattle manure.

Composting is widely adopted in livestock waste management, and the ventilation system control is essential for composting efficiency. For ventilation system, the airflow resistance is a major factor influencing the ventilation intensity and oxygen supply capacity. This study explored the variation law of airflow resistance, bulk density, specific gravity, particle size and total pressure throughout composting with cattle manure. The airflow resistance was calculated with Ergun equation, and contribution coefficients of different components were analyzed with principal component analysis (PCA). Results showed that the viscous airflow resistance was dominant throughout cattle manure composting. The average airflow resistance was 0.146 Pa/m, and resistance of pile at lower layer was higher than that at the upper layer by 18.1 %. For contribution coefficient affecting airflow resistance, the ranks were bulk density, average particle size and specific gravity. During composting process, the average airflow resistance decreased by 40.1 % and the total pressure reduced by 3.47 %. All parameters had the greatest variation at thermophilic phase, which accounted for more than 60 % of the total variation amplitude. Meanwhile, less than 10 % of the total pressure was used to overcome the airflow resistance. Therefore, reducing bulk density of pile should be considered preferentially to decrease the airflow resistance. During cattle manure composting process, the total pressure of ventilation system ought to be adjusted with the aerobic reaction to a lower level, especially at thermophilic phase with the most rapid descent rate. This study can provide support for reducing the energy consumption required for ventilation of composting.

Deletion of mesencephalic astrocyte-derived neurotrophic factor delays and damages the development of white pulp in spleen.

Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an endoplasmic reticulum (ER) stress-induced protein, and it has been reported that ER stress and unfolded protein response (UPR) are closely related to the immune system. The spleen is an important immune organ and we have shown in our previous research that MANF is expressed in human spleen tissues. However, there have been limited studies about the effect of MANF on spleen development. In this study, we detected MANF expression in spleen tissues and found that MANF was expressed in the red pulp and marginal zone. Additionally, MANF was localized in the CD68+ and CD138+ cells of adult rat spleen tissues, but not in the CD3+ cells. We performed immunohistochemical staining to detect MANF expression in the spleen tissues of rats that were different ages, and we found that MANF+ cells were localized together in the spleen tissues of rats that were 1-4 weeks old. MANF was also expressed in CD68+ cells in the spleen tissues of rats and mice. Furthermore, we found that MANF deficiency inhibited white pulp development in MANF knockout mice, thus indicating that MANF played an important role in the white pulp development of rodent spleen tissues.

Biochar addition accelerates the humification process by affecting the microbial community during human excreta composting.

Biochar addition plays an important role in manure composting, but its driving mechanism on microbial succession and humification process of human excreta composting is still unclear. In the present study, the mechanism of biochar addition was explored by analysing the humification process and microbial succession pattern of human excreta aerobic composting without and with 10% biochar (HF and BHF). Results indicated that BHF improved composting temperature, advanced the thermophilic phase by 1 d, increased the germination index by 49.03%, promoted the growth rate of humic acid content by 17.46%, and raised the compost product with the ratio of humic acid to fulvic acid (HA/FA) by 16.19%. Biochar regulated the diversity of fungi and bacteria, increasing the relative abundance of Planifilum, Meyerozyma and Melanocarpus in the thermophilic phase, and Saccharomonospora, Flavobacterium, Thermomyces and Remersonia in the mature phase, which accelerates the humification. Bacterial communities' succession had an obvious correlation with the total carbon, total nitrogen, and temperature (P < 0.05), while the succession of fungal communities was influenced by the HA/FA and pH (P < 0.05). This study could provide a reference for the improvement of on-site human excreta harmless by extending the thermophilic phase, and facilitating the humification in human excreta compost with biochar addition.

MANF Alleviates Sevoflurane-Induced Cognitive Impairment in Neonatal Mice by Modulating Microglial Activation and Polarization.

The precise mechanism underlying sevoflurane-induced neurotoxicity and cognitive impairment remains largely unknown. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a neuroprotective factor that has shown promise in various neurological disorders. However, its impact on sevoflurane-induced alterations has not been investigated. Thus, the objective of this study was to examine the effect of MANF in mitigating sevoflurane-induced neurotoxicity in young mice. Anesthesia with 3% sevoflurane 2 h daily was administered to young mice on postnatal day (P) 3, 6 and 9. We also constructed mono-macrophage-specific MANF knockout (MKO) mice in the mechanistic studies. Finally, the recombinant human MANF (rhMANF, 20 µg) protein was intraperitoneally administrated to neonatal mice before the sevoflurane anesthesia and the cognitive function, levels of pro-inflammatory cytokine and synapse-associated protein PSD95, the status of neural apoptosis, microglia activation and oxidative stress in hippocampus of the mice were investigated. The sevoflurane anesthesia increased the expression of endogenous MANF in the hippocampus, especially in microglia. MKO upregulated the expression of tumor necrosis factor-α (TNF-α), accelerated the neural apoptosis and the activation of microglia in hippocampus in young mice. MANF reversed the sevoflurane-induced cognitive impairment and inhibited the upregulation of TNF-α, the neural apoptosis and the reduction of the postsynaptic density protein-95 (PSD95) induced by sevoflurane anesthesia. Also, pretreatment with MANF alleviated the sevoflurane-induced activation of microglia and oxidative stress. Our current results demonstrated that MANF ameliorated neurotoxicity induced by the sevoflurane anesthesia in young mice, and such protective effect was associated with inhibition of microglia activation and neuroinflammation.

MANF brakes TLR4 signaling by competitively binding S100A8 with S100A9 to regulate macrophage phenotypes in hepatic fibrosis.

The mesencephalic astrocyte-derived neurotrophic factor (MANF) has been recently identified as a neurotrophic factor, but its role in hepatic fibrosis is unknown. Here, we found that MANF was upregulated in the fibrotic liver tissues of the patients with chronic liver diseases and of mice treated with CCl4. MANF deficiency in either hepatocytes or hepatic mono-macrophages, particularly in hepatic mono-macrophages, clearly exacerbated hepatic fibrosis. Myeloid-specific MANF knockout increased the population of hepatic Ly6Chigh macrophages and promoted HSCs activation. Furthermore, MANF-sufficient macrophages (from WT mice) transfusion ameliorated CCl4-induced hepatic fibrosis in myeloid cells-specific MANF knockout (MKO) mice. Mechanistically, MANF interacted with S100A8 to competitively block S100A8/A9 heterodimer formation and inhibited S100A8/A9-mediated TLR4-NF-κB signal activation. Pharmacologically, systemic administration of recombinant human MANF significantly alleviated CCl4-induced hepatic fibrosis in both WT and hepatocytes-specific MANF knockout (HKO) mice. This study reveals a mechanism by which MANF targets S100A8/A9-TLR4 as a "brake" on the upstream of NF-κB pathway, which exerts an impact on macrophage differentiation and shed light on hepatic fibrosis treatment.

EP1 activation inhibits doxorubicin-cardiomyocyte ferroptosis via Nrf2.

Chemotherapeutic agents, such as doxorubicin (DOX), may cause cardiomyopathy, even life-threatening arrhythmias in cancer patients. Ferroptosis-an iron-dependent oxidative form of programmed necrosis, plays a pivotal role in DOX-induced cardiomyopathy (DIC). Prostaglandins (PGs) are bioactive signaling molecules that profoundly modulate cardiac performance in both physiologic and pathologic conditions. Here, we found that PGE2 production and its E-prostanoid 1 receptor (EP1) expression were upregulated in erastin (a ferroptosis inducer) or DOX-treated cardiomyocytes. EP1 inhibition markedly aggravated erastin or DOX-induced cardiomyocyte ferroptosis, whereas EP1 activation exerted opposite effect. Genetic depletion of EP1 in cardiomyocytes worsens DOX-induced cardiac injury in mice, which was efficiently rescued by the ferroptosis inhibitor Ferrostatin-1 (Fer-1). Mechanistically, EP1 activation protected cardiomyocytes from DOX-induced ferroptosis by promoting nuclear factor erythroid 2-related factor 2 (Nrf2)-driven anti-oxidative gene expression, such as glutathione peroxidase 4 (GPX4) and solute carrier family 7 member 11 (SLC7A11). EP1 was coupled with Gαq to elicit intracellular Ca2+ flux and activate the PKC/Nrf2 cascade in ferroptotic cardiomyocytes. EP1 activation also prevents DOX-induced ferroptosis in human cardiomyocytes. Thus, PGE2/EP1 axis protects cardiomyocytes from DOX-induced ferroptosis by activating PKC/Nrf2 signaling and activation of EP1 may represent an attractive strategy for DIC prevention and treatment.

Relating bacterial dynamics and functions to greenhouse gas and odor emissions during facultative heap composting of four kinds of livestock manure.

Although facultative heap composting is widely used in small and medium-sized livestock farms in China, there are few studies on greenhouse gas (GHG) and odor emissions from this composting system. This study focused on GHG and odor emissions from facultative heap composting of four types of livestock manure and revealed the relationship between the gaseous emissions and microbial communities. Results showed that pig, sheep, and cow manure reached high compost maturity (germination index (GI) > 70%), whereas chicken manure had higher phytotoxicity (GI = 0.02%) with higher electrical conductivity and a lower carbon/nitrogen ratio. The four manure types significantly differed in the total GHG emission, with the following pattern: pig manure (308 g CO2-eq·kg-1) > cow manure (146 g CO2-eq·kg-1) > chicken manure (136 g CO2-eq·kg-1) > sheep manure (95 g CO2-eq·kg-1). Bacterium with Fermentative, Methanotrophy and Nitrite respiratory functions (e.g. Pseudomonas and Lactobacillus) are enriched within the pile so that more than 90% of the GHGs are produced in the early (days 0-15) and late (days 36-49) composting periods. CO2 contributed more than 90% in the first 35 d, N2O contributed 40-75% in the late composting period, and CH4 contributed less than 8.0%. NH3 and H2S emissions from chicken and pig manure were 4.8 times those from sheep and cow manure. Overall, the gas emissions from facultative heap composting significantly differed among the four manure types due to the significant differences in their physicochemical properties and microbial communities.

High oil content inhibits humification in food waste composting by affecting microbial community succession and organic matter degradation.

Composting is an effective technology to realize resource utilization of food waste in rural China. However, high oil content in food waste limits composting humification. This study investigated the effects of blended plant oil addition at different proportions (0, 10, 20, and 30%) on the humification of food waste composting. Oil addition at 10%-20% enhanced lignocellulose degradation by 16.6%-20.8% and promoted humus formation. In contrast, the high proportion of oil (30%) decreased the pH, increased the electrical conductivity, and reduced the seed germination index to 64.9%. High-throughput sequencing showed that high oil inhibited the growth and reproduction of bacteria (Bacillus, Fodinicurvataceae, and Methylococcaceae) and fungi (Aspergillus), attenuated their interaction, thus, reducing the conversion of organic matter, such as lignocellulose, fat, and total sugar, to humus, consequently leading to negative impacts on composting humification. The results can guide composting parameter optimization and improve effective management of rural food waste.

Renin-angiotensin system inhibition and in-hospital mortality in acute coronary syndrome patients with advanced renal dysfunction: findings from CCC-ACS project and a nationwide electronic health record-based cohort in China.

AIMS: In acute coronary syndrome (ACS) patients without advanced renal dysfunction [estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2], early (within 24 h of admission) angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (ACEI/ARB) is the guideline-directed medical therapy. The clinical efficacy of early ACEI/ARB therapy among ACS patients with advanced renal dysfunction remains unclear. METHODS AND RESULTS: Among 184 850 ACS patients hospitalized from July 2014 to December 2018 in the Chinese National Electronic Disease Surveillance System Platform (CNEDSSP) cohort and 113 650 ACS patients enrolled from November 2014 to December 2019 in the Improving Care for Cardiovascular Disease in China-ACS Project (CCC-ACS) cohort, we identified 3288 and 3916 ACS patients with admission eGFR < 30 mL/min/1.73 m2 [2647 patients treated with ACEI/ARB (36.7%)], respectively. After 1:1 propensity score matching (PSM) in each cohort, Kaplan-Meier analysis showed that early ACEI/ARB use was associated with a 39% [hazard ratio (HR): 0.61, 95% confidence interval (95% CI): 0.45-0.82] and a 34% (HR: 0.66, 95% CI: 0.46-0.95) reduction in in-hospital mortality in CNEDSSP and CCC-ACS cohorts, respectively, which was consistent in multiple sensitivity analyses. A random effect meta-analysis of the two cohorts after PSM revealed a 32% reduction (risk ratio: 0.68, 95% CI: 0.55-0.84) in in-hospital mortality among ACEI/ARB users. CONCLUSIONS: Based on two nationwide cohorts in China in contemporary practice, we demonstrated that ACEI/ARB therapy initiated within 24 h of admission is associated with a reduction in in-hospital mortality in ACS patients with advanced renal dysfunction. CLINICAL TRIAL REGISTRATION: CCC-ACS project was registered at URL: https://www.clinicaltrials.gov. (Unique identifier: NCT02306616).

Hepatocyte-derived MANF mitigates ethanol-induced liver steatosis in mice via enhancing ASS1 activity and activating AMPK pathway.

Hepatic steatosis plays a detrimental role in the onset and progression of alcohol-associated liver disease (ALD). Mesencephalic astrocyte-derived neurotrophic factor (MANF) is an evolutionarily conserved protein related to the unfolded protein response. Recent studies have demonstrated that MANF plays an important role in liver diseases. In this study, we investigated the role of MANF in ethanol-induced steatosis and the underlying mechanisms. We showed that the hepatic MANF expression was markedly upregulated in mouse model of ALD by chronic-plus-single-binge ethanol feeding. Moreover, after chronic-plus-binge ethanol feeding, hepatocyte-specific MANF knockout (HKO) mice displayed more severe hepatic steatosis and liver injury than wild-type (WT) control mice. Immunoprecipitation-coupled MS proteomic analysis revealed that arginosuccinate synthase 1 (ASS1), a rate-limiting enzyme in the urea cycle, resided in the same immunoprecipitated complex with MANF. Hepatocyte-specific MANF knockout led to decreased ASS1 activity, whereas overexpression of MANF contributed to enhanced ASS1 activity in vitro. In addition, HKO mice displayed unique urea cycle metabolite patterns in the liver with elevated ammonia accumulation after ethanol feeding. ASS1 is known to activate AMPK by generating an intracellular pool of AMP from the urea cycle. We also found that MANF supplementation significantly ameliorated ethanol-induced steatosis in vivo and in vitro by activating the AMPK signaling pathway, which was partly ASS1 dependent. This study demonstrates a new mechanism in which MANF acts as a key molecule in maintaining hepatic lipid homeostasis by enhancing ASS1 activity and uncovers an interesting link between lipid metabolism and the hepatic urea cycle under excessive alcohol exposure.

PRDX6 Promotes Fatty Acid Oxidation via PLA2-Dependent PPARα Activation in Rats Fed High-Fat Diet.

Aims: Nonalcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease globally, which is defined as an excess accumulation of fat caused by the imbalance of lipogenesis and lipid catabolism. Recently, increasing evidence suggests that peroxiredoxin 6 (PRDX6) is involved in the pathogenesis and progression of NAFLD. However, little is known regarding its role in liver lipid catabolism. Results: We found that PRDX6 level was significantly increased in liver tissues after high-fat diet (HFD) treatment. PRDX6 knockout (KO) exacerbated HFD-induced hepatic steatosis. PRDX6 KO did not affect messenger RNA (mRNA) and protein levels of peroxisome proliferator-activated receptor alpha (PPARα). However, PRDX6 KO decreased the mRNA and protein levels of carnitine palmitoyltransferase-1alpha (CPT-1α) and acyl-CoA oxidase 1 (ACOX1), the target genes of PPARα. PRDX6 KO also did not activate AMP-activated protein kinase (AMPK)α/proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), the upstream signal of PPARα. However, PRDX6 KO reduces the levels of PPARα activators, the oxidized fatty acids (9- and 13-hydroxyoctadecadienoic acid) in HFD rats. More interestingly, PRDX6 promoted the production of oxidized fatty acids by hydrolyzing oxidized low-density lipoprotein (Ox-LDL), which depends on its phospholipase A2 (PLA2) activity. PRDX6 mutation on its PLA2 and its competitive phospholipase inhibitor inhibited the production of the oxidized fatty acids as well as the activation of PPARα. Furthermore, PRDX6 overexpression enhanced the transcriptional activation of PPARα. Innovation and Conclusion: This study elucidates for the first time the role of PLA2 enzyme activity of PRDX6 in fatty acid oxidation and reveals a novel mechanism of PRDX6 involved in liver steatosis. Antioxid. Redox Signal. 38, 1184-1200.

GH-Feat: Learning Versatile Generative Hierarchical Features From GANs.

Recent years witness the tremendous success of generative adversarial networks (GANs) in synthesizing photo-realistic images. GAN generator learns to compose realistic images and reproduce the real data distribution. Through that, a hierarchical visual feature with multi-level semantics spontaneously emerges. In this work we investigate that such a generative feature learned from image synthesis exhibits great potentials in solving a wide range of computer vision tasks, including both generative ones and more importantly discriminative ones. We first train an encoder by considering the pre-trained StyleGAN generator as a learned loss function. The visual features produced by our encoder, termed as Generative Hierarchical Features (GH-Feat), highly align with the layer-wise GAN representations, and hence describe the input image adequately from the reconstruction perspective. Extensive experiments support the versatile transferability of GH-Feat across a range of applications, such as image editing, image processing, image harmonization, face verification, landmark detection, layout prediction, image retrieval, etc. We further show that, through a proper spatial expansion, our developed GH-Feat can also facilitate fine-grained semantic segmentation using only a few annotations. Both qualitative and quantitative results demonstrate the appealing performance of GH-Feat. Code and models are available at https://genforce.github.io/ghfeat/.

Xanthatin suppresses proliferation and tumorigenicity of glioma cells through autophagy inhibition via activation of the PI3K-Akt-mTOR pathway.

Glioma is the most common and aggressive primary brain tumor in adults with high morbidity and mortality. Rapid proliferation and diffuse migration are the main obstacles to successful glioma treatment. Xanthatin, a sesquiterpene lactone purified from Xanthium strumarium L., possesses a significant antitumor role in several malignant tumors. In this study, we report that xanthatin suppressed glioma cells proliferation and induced apoptosis in a time- and concentration-dependent manner, and was accompanied by autophagy inhibition displaying a significantly reduced LC3 punctate fluorescence and LC3II/I ratio, decreased level of Beclin 1, while increased accumulation of p62. Notably, treating glioma cells with xanthatin resulted in obvious activation of the PI3K-Akt-mTOR signaling pathway, as indicated by increased mTOR and Akt phosphorylation, decreased ULK1 phosphorylation, which is important in modulating autophagy. Furthermore, xanthatin-mediated pro-apoptosis in glioma cells was significantly reversed by autophagy inducers (rapamycin or Torin1), or PI3K-mTOR inhibitor NVP-BEZ235. Taken together, these findings indicate that anti-proliferation and pro-apoptosis effects of xanthatin in glioma are most likely by inhibiting autophagy via activation of PI3K-Akt-mTOR pathway, suggesting a potential therapeutic strategy against glioma.

Targeting the DP2 receptor alleviates muscle atrophy and diet-induced obesity in mice through oxidative myofiber transition.

BACKGROUND: Mammalian skeletal muscles consist of two main fibre types: slow-twitch (type I, oxidative) and fast-twitch (type IIa, fast oxidative; type IIb/IIx, fast glycolytic). Muscle fibre composition switch is closely associated with chronic diseases such as muscle atrophy, obesity, type II diabetes and athletic performance. Prostaglandin D2 (PGD2 ) is a bioactive lipid derived from arachidonic acid that aggravates muscle damage and wasting during muscle atrophy. This study aimed to investigate the precise mechanisms underlying PGD2 -mediated muscle homeostasis and myogenesis. METHODS: Skeletal muscle-specific PGD2 receptor DP2-deficient mice (DP2fl/fl HSACre ) and their littermate controls (DP2fl/fl ) were subjected to exhaustive exercise and fed a high-fat diet (HFD). X-linked muscular dystrophy (MDX) mice and HFD-challenged mice were treated with the selective DP2 inhibitor CAY10471. Exercise tolerance, body weight, glycometabolism and skeletal muscle fibre composition were measured to determine the role of the skeletal muscle PGD2 /DP2 signalling axis in obesity and muscle disorders. Multiple genetic and pharmacological approaches were also used to investigate the intracellular signalling cascades underlying the PGD2 /DP2-mediated skeletal muscle fibre transition. RESULTS: PGD2 generation and DP2 expression were significantly upregulated in the hindlimb muscles of HFD-fed mice (P < 0.05 or P < 0.01 vs. normal chow diet). Compared with DP2fl/fl mice, DP2fl/fl HSACre mice exhibited remarkable glycolytic-to-oxidative fibre-type transition in hindlimb muscles and were fatigue resistant during endurance exercise (154.9 ± 6.0 vs. 124.2 ± 8.1 min, P < 0.05). DP2fl/fl HSACre mice fed an HFD showed less weight gain (P < 0.05) and hepatic lipid accumulation (P < 0.01), reduced insulin resistance and enhanced energy expenditure (P < 0.05) compared with DP2fl/fl mice. Mechanistically, DP2 deletion promoted the nuclear translocation of nuclear factor of activated T cells 1 (NFATc1) by suppressing RhoA/Rho-associated kinase 2 (ROCK2) signalling, which led to enhanced oxidative fibre-specific gene transcription in muscle cells. Treatment with CAY10471 enhanced NFATc1 activity in the skeletal muscles and ameliorated HFD-induced obesity (P < 0.05 vs. saline) and insulin resistance in mice. CAY10471 also enhanced exercise tolerance in MDX mice (100.8 ± 8.0 vs. 68.9 ± 11.1 min, P < 0.05 vs. saline) by increasing the oxidative fibre-type ratio in the muscles (45.1 ± 2.3% vs. 32.3 ± 2.6%, P < 0.05 vs. saline). CONCLUSIONS: DP2 activation suppresses oxidative fibre transition via RhoA/ROCK2/NFATc1 signalling. The inhibition of DP2 may be a potential therapeutic approach against obesity and muscle disorders.