The influence of dietary Coenzyme Q10 on growth performance, antioxidant capacity and resistance against Aeromonas hydrophila of juvenile European eel (Anguilla anguilla).

The present study was conducted to investigate the effects of dietary Coenzyme Q10 (CoQ10) on the growth performance, body composition, digestive enzyme activity, antioxidant capacity, intestinal histology, immune-antioxidant gene expression and disease resistance of juvenile European eel (Anguilla anguilla). Fish were fed a diet supplemented with CoQ10 at concentrations of 0, 40, 80 and 120 mg/kg for 56 days. The results indicated that dietary CoQ10 supplementation did not significantly affect final body weight (FBW), survival rate (SR), weight gain (WG), feed rate (FR), viscerosomatic index (VSI) or hepatosomatic index (HSI) among all experimental groups. However, the highest FBW, WG and SR were found in the 120 mg/kg CoQ10 group. Dietary 120 mg/kg CoQ10 markedly improved feed efficiency (FE) and the protein efficiency ratio (PER). The crude lipid in the body and triglycerides (TG) and total cholesterol (TC) in serum were obviously lower in the 120 mg/kg CoQ10 group than in the control group. For digestive enzymes, protease activity in the intestine was markedly boosted in the 120 mg/kg CoQ10 group. The serum activities of SOD, CAT and GST in the 120 mg/kg CoQ10 group were significantly higher than those in the control group. Dietary 120 mg/kg CoQ10 efficiently enhanced superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione S-transferase (GST) activities in the liver, while the malondialdehyde (MDA) content was significantly decreased. No significant histological changes in the liver were identified in any group. Dietary supplementation with 120 mg/kg CoQ10 improved antioxidant capacity and immunity by upregulating the expression of cyp1a, sod, gst, lysC, igma1, igmb1 and irf3 in the liver. Furthermore, the cumulative survival rate of juvenile European eel against challenge with Aeromonas hydrophila was significantly elevated in the 80 and 120 mg/kg CoQ10 supplemented groups. Conclusively, our study suggested that supplementing the diet of juvenile European eel with CoQ10 at a concentration of 120 mg/kg could promote their feed utilization, fat reduction, antioxidant capacity, digestibility, immune-antioxidant gene expression and resistance to Aeromonas hydrophila without negative effects on fish health status.

Metformin enhances neural precursor cells migration and functional recovery after ischemic stroke in mice.

Resident neural precursor cells (NPCs) activation is a promising therapeutic strategy for brain repair. This strategy involves stimulating multiple stages of NPCs development, including proliferation, self-renewal, migration, and differentiation. Metformin, an FDA-approved diabetes drug, has been shown to promote the proliferation and differentiation of NPCs. However, it is still unclear whether metformin promotes the migration of NPCs. EVOS living cell imaging system was used for observing the migration for primary NPCs dynamically in vitro after metformin treatment. For in vivo study, a mouse model of ischemic stroke was established through middle cerebral artery occlusion (MCAO). To label the proliferating cell in subventricular zone, BrdU was injected intraperitoneally into the mice. After co-staining with BrdU and doublecortin (DCX), a marker for NPCs, the migration of Brdu and DCX double positive NPCs was detected along the rostral migratory stream (RMS) and around the infarct area using frozen brain sections. Finally, the rotarod test, corner test and beam walking were performed to evaluate the motor functions of the mice after stroke in different groups. The results showed that metformin enhanced NPCs migration in vivo and in vitro by promoting F-actin assembly and lamellipodia formation. What's more, metformin treatment also significantly reduced the infarct volume and alleviated functional dysfunction after stroke. Mechanistically, metformin promoted NPCs migration via up-regulating the CDC42 expression. Taken together, metformin represents an optimal candidate agent for neural repair that is capable of not only expanding the adult NPC population but also subsequently driving them toward the destination for neuronal differentiation.

Angiogenic Activity and Mechanism for Bisphenols on Endothelial Cell and Mouse: Evidence of a Structural-Selective Effect.

Increased epidemiological evidence indicates the association of bisphenol exposure with human vascular disorders, while the underlying mechanism has not been clarified. Here, we sought to unveil the potential angiogenic effect and the underlying mechanism of bisphenols with different structural features using endothelial cells treated with an environmentally relevant concentration of bisphenols (range: 1 nM to 10 µM) and a C57BL/6 mouse model fed with doses of 0.002, 0.02, 2, and 20 mg/kg BW/day for 5 weeks. Bisphenol A (BPA) and bisphenol S (BPS) at a 1 nM level significantly increased tube formation by 45.1 and 30.2% and induced the microvessel sprouting, while tube length and microvessel sprouting were significantly inhibited by 37.2 and 55.7% after exposure to tetrabromobisphenol S (TBBPS) at 1 µM, respectively. Mechanistically, TBBPA and TBBPS significantly inhibited the interaction between phosphatidylinositol 3-kinase (PI3K) and thyroid receptor (TR), while BPA and BPS favored the interaction between PI3K and estrogen receptor (ER), resulting in abnormal PI3K signaling with consequent distinct angiogenic activity. BPA- and BPS-induced pro-angiogenic effects and TBBPS showed anti-angiogenic effects due to their distinct disruption on the TR/ER-PI3K pathway. Our work provided new evidence and mechanistic insight on the angiogenic activity of bisphenols and expanded the scope of endocrine disruptors with interference in vascular homeostasis.

Genetic association of telomere length, obesity and tobacoo smoking with idiopathic pulmonary fibrosis risk.

BACKGROUND: Due to the inadequacy of published evidence, association of telomere length (TL), obesity and tobacco smoking with idiopathic pulmonary fibrosis (IPF) remains unclear. The aim of the study was to explore whether these exposures genetically affected the risk of the disease. METHODS: Genetic variants from genome-wide association studies for TL, body mass index (BMI), body fat percentage (BFP) and tobacco smoking (including maternal smoking) were used as instrumental variables. Inverse-variance weighted were mainly adopted to determine the genetic association of these exposures with IPF. All analyses were conducted by R-software (version 3.6.1). RESULTS: Firstly, longer TL was associated with the decreased risk of IPF (OR = 0.475 per SD increase in TL, 95%CI = 0.336 ~ 0.670, P<0.001). Secondly, higher levels of BMI and BFP were related to the increased risk of the disease (OR = 1.425 per SD increase in BMI level, 95%CI = 1.114 ~ 1.823, P = 0.005; OR = 1.702 per SD increase in BFP level, 95%CI = 1.202 ~ 2.409, P = 0.003). Thirdly, maternal smoking was implicated in the increased risk of the disease (OR = 13.183 per SD increase in the prevalence of maternal smoking, 95%CI = 1.820 ~ 95.484, P = 0.011). CONCLUSION: TL should be a genetic risk factor for IPF. Obesity and exposure to tobacco smoking as a fetus might also contribute to the development of this fibrotic diseases. These findings should be verified by future studies.

Efficacy and Safety of High-intensity Focused Ultrasound Compared with Uterine Artery Embolization in Cesarean Section Pregnancy: A Meta-analysis.

OBJECTIVE: To investigate the efficacy and safety of high-intensity focused ultrasound (HIFU) compared with uterine artery embolization (UAE) in cesarean section pregnancy (CSP) and to calculate the success rate of HIFU. DATA SOURCES: We searched PubMed, Cochrane, Scopus, Web of Science, and Embase on September 30, 2022, and the related studies were independently reviewed by 2 researchers. METHODS OF STUDY SELECTION: Medical subject headings and relevant terms from other articles were used for the database search. Patients with CSP who underwent HIFU were included in this analysis. The following results were recorded: success rate, intraoperative blood loss, time for serum beta-human chorionic gonadotropin (beta-HCG) normalization and menstruation recovery, adverse events, hospitalization time, and hospitalization expenses. We used the Newcastle-Ottawa Scale scoring system and the methodological index for nonrandomized studies system to evaluate the quality of the studies. TABULATION, INTEGRATION, AND RESULTS: Data from 6 studies were used to compare the efficacy and safety of UAE and HIFU. We pooled the success rate of HIFU by including 10 studies. No data overlap between the 10 studies. Success rate was higher in the HIFU group (odds ratio [OR] = 1.90; 95% confidence interval [CI] 1.06-3.41; p = .03; I2 = 0). We performed the meta-analysis of single rate in R 4.2.0 software, and the success rate of HIFU group was 0.94 (95% CI 0.92-0.96; p = .04; I2 = 48%). Intraoperative blood loss (mean difference [MD]= -21.94 mL; 95% CI -67.34 to 23.47; p = .34; I2 = 99%) and time for serum beta-HCG normalization (MD = 3.13 days; 95% CI 0.02-6.25; p = .05; I2 = 70%) were not significantly different. Time to menstruation recovery (MD = 2.72 days; 95% CI 1.32-4.12; p = .0001; I2 = 0) in the UAE group was shorter than that in the HIFU group. Adverse events were not significantly different between the 2 groups (OR = 0.53; 95% CI 0.22-1.29; p = .16; I2 = 81%). Hospitalization time was not significantly different between the HIFU and UAE groups (MD = -0.41 days; 95% CI -1.14 to 0.31; p = .26; I2 = 55%). Hospitalization expenses of the HIFU group were lower than those of the UAE group (MD = -7488.49 yuan; 95% CI -8460.13 to -6516.84; p <.000; I2 = 0). Heterogeneity of the time for beta-HCG normalization, adverse events, and hospitalization time were improved after excluding one study, and HIFU showed better results in the sensitivity analysis of adverse events and hospitalization time. CONCLUSION: According to our analysis, HIFU demonstrated satisfactory treatment success, accompanied by similar intraoperative blood loss, slower normalization of beta-HCG levels, and menstruation recovery, but potentially shorter hospitalization time, lower adverse events and lower costs than UAE. Therefore, HIFU is an effective, safe, and economical treatment for patients with CSP. These conclusions should be interpreted with caution because of the significant heterogeneity. However, large and strictly designed clinical trials are required to verify these conclusions.

Resveratrol attenuated oxidative stress and inflammatory and mitochondrial dysfunction induced by acute ammonia exposure in gibel carp (Carassius gibelio).

Ammonia is recognized as an environmental stressor for fish. As resveratrol (RES) has anti-inflammatory and antioxidant properties, we hypothesized that RES could attenuate the response to ammonia exposure in gibel carp. Therefore, gibel carp were fed a diet containing RES for eight weeks, followed by acute ammonia stimulation. Stress induced by acute ammonia exposure could be ameliorated by RES, manifested by down-regulated plasma glucose, and up-regulated C3 and IgM levels. Furthermore, decreased AST and LDH; enhanced T-AOC, SOD, and GPx in the liver; and reduced damage to gill and liver tissues indicated that RES attenuated oxidative and tissue damage induced by ammonia exposure. Moreover, RES activated the Nrf2/HO-1 pathway and up-regulated the expression of several antioxidant genes. RES enhanced anti-inflammatory activity as reflected by activation of the NF-κB pathway, down-regulated the expression of pro-inflammatory cytokines (nfκb, tnf-α, and il-1ß), and up-regulated the expression of anti-inflammatory cytokines (il-4 and il-10). In terms of mitochondrial function, RES up-regulated protein levels of p-AMPK, SIRT1, and PGC-1α; inhibited mitochondrial fission; promoted mitochondrial fusion and biogenesis-related gene expression. Overall, the results suggest that RES mediated the Nrf2/HO-1, NF-κB, and AMPK/SIRT1/PGC-1α pathways to attenuate oxidative stress, inflammation, and mitochondrial dysfunction induced by ammonia in gibel carp.

Anomaly Detection via Progressive Reconstruction and Hierarchical Feature Fusion.

The main challenges in reconstruction-based anomaly detection include the breakdown of the generalization gap due to improved fitting capabilities and the overfitting problem arising from simulated defects. To overcome this, we propose a new method called PRFF-AD, which utilizes progressive reconstruction and hierarchical feature fusion. It consists of a reconstructive sub-network and a discriminative sub-network. The former achieves anomaly-free reconstruction while maintaining nominal patterns, and the latter locates defects based on pre- and post-reconstruction information. Given defective samples, we find that adopting a progressive reconstruction approach leads to higher-quality reconstructions without compromising the assumption of a generalization gap. Meanwhile, to alleviate the network's overfitting of synthetic defects and address the issue of reconstruction errors, we fuse hierarchical features as guidance for discriminating defects. Moreover, with the help of an attention mechanism, the network achieves higher classification and localization accuracy. In addition, we construct a large dataset for packaging chips, named GTanoIC, with 1750 real non-defective samples and 470 real defective samples, and we provide their pixel-level annotations. Evaluation results demonstrate that our method outperforms other reconstruction-based methods on two challenging datasets: MVTec AD and GTanoIC.

Effects of Curcumin on Oxidative Stress and Ferroptosis in Acute Ammonia Stress-Induced Liver Injury in Gibel Carp (Carassius gibelio).

This study investigated the potential role of curcumin (CUR) in preventing oxidative stress and ferroptosis induced by ammonia exposure in gibel carp. Experimental fish (initial weight: 11.22 ± 0.10 g, n = 150) were fed diets supplemented with or without 0.5% CUR for 56 days, followed by a 24 h ammonia (32.5 mg/L) exposure. Liver damages (aspartate aminotransferase (AST), alanine aminotransferase (ALT), adenosine deaminase (ADA), and alkaline phosphatase (ALP)) and oxidative stress enzyme activities (reactive oxygen species (ROS), malondialdehyde (MDA); and the content of antioxidant capacity (T-AOC), superoxide dismutase (SOD), and glutathione peroxidase (GPx)) were induced by ammonia stress. The antioxidant capacity was decreased, as indicated by inhibited gene expression of nuclear factor erythroid 2-related factor 2 (nrf2), heme oxygenase-1 (ho-1), catalase (cat), and sod. Ferroptosis was induced by ammonia stress, as suggested by upregulated mRNA levels of nuclear receptor coactivator 4 (ncoa4), transferrin receptor 1 (tfr1), and iron-responsive element-binding protein 2 (ireb2), and downregulated expression of glutathione peroxidase 4 (gpx4), ferroportin (fpn), and ferritin heavy chain 1 (fth1). In addition, both mRNA and protein levels of ferroptosis markers acyl-CoA synthetase long-chain family member 4 (ACSL4) and prostaglandin-endoperoxide synthase 2 (PTGS2) were upregulated, while cystine/glutamate antiporter (SLC7A11) was downregulated. However, liver injury and ferroptosis in fish induced by ammonia could be attenuated by CUR. Collectively, these findings demonstrate that CUR ameliorates oxidative stress and attenuates ammonia stress-induced ferroptosis. This study provides a new perspective on potential preventive strategies against ammonia stress in gibel carp by dietary CUR.

Novel Functionalized Boron Nitride Nanosheets Achieved by Radiation-Induced Oxygen Radicals and Their Enhancement for Polymer Nanocomposites.

Boron nitride nanosheets (BNNSs) exfoliated from hexagonal boron nitride (h-BN) show great potential in polymer-based composites due to their excellent mechanical properties, highly thermal conductivity, and insulation properties. Moreover, the structural optimization, especially the surface hydroxylation, of BNNSs is of importance to promote their reinforcements and optimize the compatibility of its polymer matrix. In this work, BNNSs were successfully attracted by oxygen radicals decomposed from di-tert-butylperoxide (TBP) induced by electron beam irradiation and then treated with piranha solution. The structural changes of BNNSs in the modification process were deeply studied, and the results demonstrate that the as-prepared covalently functionalized BNNSs possess abundant surface hydroxyl groups as well as reliable structural integrity. Of particular importance is that the yield rate of the hydroxyl groups is impressive, whereas the usage of organic peroxide and reaction time is greatly reduced due to the positive effect of the electron beam irradiation. The comparisons of PVA/BNNSs nanocomposites further indicate that the hydroxyl-functionalized BNNSs effectively promote mechanical properties and breakdown strength due to the enhanced compatibility and strong two-phase interactions between nanofillers and the polymer matrix, which further verify the application prospects of the novel route proposed in this work.

Ultrasensitive and Simple Dopamine Electrochemical Sensor Based on the Synergistic Effect of Cu-TCPP Frameworks and Graphene Nanosheets.

Dopamine (DA) is an important neurotransmitter. Abnormal concentration of DA can result in many neurological diseases. Developing reliable determination methods for DA is of great significance for the diagnosis and monitoring of neurological diseases. Here, a novel and simple electrochemical sensing platform for quantitative analysis of DA was constructed based on the Cu-TCPP/graphene composite (TCPP: Tetrakis(4-carboxyphenyl)porphyrin). Cu-TCPP frameworks were selected in consideration of their good electrochemical sensing potential. The graphene nanosheets with excellent conductivity were then added to further improve the sensing efficiency and stability of Cu-TCPP frameworks. The electrochemical properties of the Cu-TCPP/graphene composite were characterized, showing its large electrode active area, fast electron transfer, and good sensing performance toward DA. The signal enhancement mechanism of DA was explored. Strong accumulation ability and high electrocatalytic rate were observed on the surface of Cu-TCPP/graphene-modified glassy carbon electrode (Cu-TCPP/graphene/GCE). Based on the synergistic sensitization effect, an ultrasensitive and simple DA electrochemical sensor was developed. The linear range is 0.02-100 and 100-1000 µM, and the detection limit is 3.6 nM for the first linear range. It was also successfully used in detecting DA in serum samples, and a satisfactory recovery was obtained.

Data Mining Evidences Variabilities in Glucose and Lipid Metabolism among Fish Strains: A Case Study on Three Genotypes of Gibel Carp Fed by Different Carbohydrate Sources.

An 8-week feeding trial was conducted to evaluate the application of common carbohydrate sources, cornstarch (CS), wheat starch (WS), and wheat flour (WF), to different gibel carp genotypes, Dongting, CASIII, and CASV. The results of the growth and physical responses were analysed by data visualization and unsupervised machine learning. As revealed by a self-organizing map (SOM) and the cluster of growth and biochemical indicators, CASV had superior growth and feed utilization and better regulation of postprandial glucose, followed by CASIII, while Dongting showed a high level of plasma glucose with poor growth performance. CS, WS, and WF were differently utilized by the gibel carp, and WF was associated with greater zootechnical performance based on higher specific growth rate (SGR), feed efficiency (FE), protein retention efficiency (PRE), and lipid retention efficiency (LRE), induced hepatic lipogenesis, increased liver lipids, and enhanced muscle glycogen. Spearman's correlation analysis of the physiological responses indicated that plasma glucose had a significantly negative correlation with growth, feed utilization, glycogen storage, and plasma cholesterol level, and it was positively related to liver fat content in gibel carp. Transcriptional variabilities were observed: CASIII showed increased expression of pklr, which is involved in hepatic glycolysis, and pck and g6p, which are involved in gluconeogenesis. Interestingly, Dongting showed upregulation of genes involved in glycolysis and fatty acid oxidation in muscle. Furthermore, there were numerous interactions between carbohydrate sources and strains for growth, metabolites, and transcriptional control, confirming the existence of genetic polymorphisms in carbohydrate use in gibel carp. Globally, CASV showed relatively better growth and carbohydrate utilization, and wheat flour seemed to be more efficiently utilized by gibel carp.

Effects of Different Dietary Selenium Sources on the Meat Quality and Antioxidant Capacity of Yellow Catfish (Pelteobagrus fulvidraco).

To assess the effect of dietary selenium (Se) sources on the meat quality and antioxidant capacity of yellow catfish (Pelteobagrus fulvidraco), sodium selenite (Na2SeO3), Se yeast, and selenium-enriched Spirulina platensis (Se-SP) were supplemented in the control diet at 0.30 mg Se/kg feed to formulate four diets. The experimental period lasted 50 days. The results showed that Se levels in the plasma, liver, muscle, and whole body were significantly increased by dietary Se yeast supplementation (P < 0.05) but showed no change in response to Na2SeO3 (P > 0.05). The three types of Se all increased the firmness and decreased the fracturability of the muscles (P < 0.05), but only Na2SeO3 resulted in higher springiness, flexibility, stringiness, and stickiness (P < 0.05). In addition, the muscle n-3 polyunsaturated fatty acid (PUFA) content was increased by Se yeast (P < 0.05). Regarding antioxidant capacity, dietary Se yeast and Se-SP supplementation improved hepatic glutathione peroxidase activity but decreased hepatic malondialdehyde content (P < 0.05). Given these results, Se yeast was found to be the optimal source of Se for yellow catfish for higher tissue retention, antioxidant capacity, and PUFA levels. Dietary Se is an effective way to regulate the meat quality and antioxidant capacity of yellow catfish.

Sequential Activations of ChREBP and SREBP1 Signals Regulate the High-Carbohydrate Diet-Induced Hepatic Lipid Deposition in Gibel Carp (Carassius gibelio).

The present study investigated the sequential regulation signals of high-carbohydrate diet (HCD)-induced hepatic lipid deposition in gibel carp (Carassius gibelio). Two isonitrogenous and isolipidic diets, containing 25% (normal carbohydrate diet, NCD) and 45% (HCD) corn starch, were formulated to feed gibel carp (14.82 ± 0.04 g) for 8 weeks. The experimental fish were sampled at 2nd, 4th, 6th, and 8th week. In HCD group, the hyperlipidemia and significant hepatic lipid deposition (oil red O area and triglyceride content) was found at 4th, 6th, and 8th week, while the significant hyperglycemia was found at 2nd, 4th, and 8th week, compared to NCD group (P < 0.05). HCD induced hepatic lipid deposition via increased hepatic lipogenesis (acc, fasn, and acly) but not decreased hepatic lipolysis (hsl and cpt1a). When compared with NCD group, HCD significantly elevated the hepatic sterol regulatory element binding proteins 1 (SREBP1) signals (positive hepatocytes and fluorescence intensity) at 4th, 6th, and 8th week (P < 0.05). The hepatic SREBP1 signals increased from 2nd to 6th week, but decreased at 8th week due to substantiated insulin resistance (plasma insulin levels, plasma glucose levels, and P-AKTSer473 levels) in HCD group. Importantly, the hepatic carbohydrate response element binding protein (ChREBP) signals (positive hepatocytes, fluorescence intensity, and expression levels) were all significantly elevated by HCD-induced glucose-6-phosphate (G6P) accumulation at 2nd, 4th, 6th, and 8th week (P < 0.05). Compared to 2nd and 4th week, the hepatic ChREBP signals and G6P contents was significantly increased by HCD at 6th and 8th week (P < 0.05). The HCD-induced G6P accumulation was caused by the significantly increased expression of hepatic gck, pklr, and glut2 (P < 0.05) but not 6pfk at 4th, 6th, and 8th week, compared to NCD group. These results suggested that the HCD-induced hepatic lipid deposition was mainly promoted by SREBP1 in earlier stage and by ChREBP in later stage for gibel carp. This study revealed the sequential regulation pathways of the conversion from feed carbohydrate to body lipid in fish.

Compared to Fishmeal, Dietary Soybean Meal Improves the Reproductive Performance of Female Yellow Catfish (Pelteobagrus fulvidraco) Broodstock.

To investigate the effects of different dietary protein sources on the reproductive performance of female broodstock, yellow catfish (Pelteobagrus fulvidraco) were fed with three experimental diets using fishmeal (FM), soybean meal (SBM), and rapeseed meal (RSM) as main protein sources, respectively. Females (initial weight: 64.56 ± 0.45 g) were distributed into 9 net cages for feeding trial. Results indicated that 30% dietary SBM improved the reproductive performance for higher gonadosomatic index (GSI), relative fecundity, total egg production, egg diameter, and hatching rate. In addition, SBM and RSM diets resulted in higher estradiol (E2), vitellogenin (VTG), luteinizing hormones (LH), and lower follicle-stimulating hormone (FSH) and testosterone (T) in plasma (P < 0.05) of female broodstock. Dietary SBM and RSM also resulted in lower mesenteric fat index (MFI), plasma total cholesterol (TC), plasma total bilirubin (T-Bil) contents, and gonadal cortisol concentrations, while dietary SBM downregulated the transcription levels of steroidogenesis-related proteins by negative feedback (P < 0.05). The results demonstrated that dietary SBM and RSM could promote sex steroid hormone and VTG biosynthesis and showed hypocholesterolemic effects. Besides, 30% dietary SBM inclusion could improve the reproductive performance of female yellow catfish broodstock.

Study on Carbohydrate Metabolism in Adult Zebrafish (Danio rerio).

Excessive carbohydrate intake leads to metabolic disorders in fish. However, few literatures have reported the appropriate carbohydrate level for zebrafish, and the metabolic response to dietary carbohydrate remains largely unknown in zebrafish. This study assessed the responses of zebrafish and zebrafish liver cell line (ZFL) to different carbohydrate levels. In vivo results showed that ≥30% dietary dextrin levels significantly increased the plasma glucose content, activated the expression of hepatic glycolysis-related genes, and inhibited the expression of hepatic gluconeogenesis-related genes in zebrafish. Oil red O staining, triglyceride content, and Hematoxylin-Eosin staining results showed that dietary dextrin levels of ≥30% significantly increased lipid accumulation and liver damage, as well as processes related to glycolipid metabolism and inflammation in zebrafish. In ZFL, the transcription factor sterol regulatory element binding protein-1c signal intensity, 4,4-difluoro-1,3,5,7,8-pentamethyl-4-bora-3a,4a-diaza-s-indacene (BODIPY 493/503) signal intensity, and triglyceride content were also significantly increased when incubated in high glucose, along with abnormal glycolipid metabolism and increased inflammation-related genes. In conclusion, we demonstrated that the maximum dietary carbohydrate level in adult zebrafish should be less than 30%. Excess dietary carbohydrates (30%-50%) caused hepatic steatosis and damage to zebrafish, similar to that seen in aquaculture species. Thus, this study assessed responses to different carbohydrate levels in zebrafish and illustrated that zebrafish is an optimal model for investigating glucose metabolism in some aquatic animals.

MEC17-induced α-tubulin acetylation restores mitochondrial transport function and alleviates axonal injury after intracerebral hemorrhage in mice.

Injury to long axonal projections is a central pathological feature at the early phase of intracerebral hemorrhage (ICH). It has been reported to contribute to persistent functional disability following ICH. However, the molecular mechanisms that drive axonal degeneration remain unclear. Autologous blood was injected into the striatum to mimic the pathology of ICH. Observed significant swollen axons with characteristic retraction bulbs were found around the striatal hematoma at 24 h after ICH. Electronic microscopic examination revealed highly disorganized microtubule and swollen mitochondria in the retraction bulbs. MEC17 is a specific α-tubulin acetyltransferase, ablation of acetylated α-tubulin in MEC17-/- mice aggravated axonal injury, axonal transport mitochondria dysfunction, and motor dysfunction. In contrast, treatment with tubastatin A (TubA), which promotes microtubule acetylation, significantly alleviated axonal injury and protected the integrity of the corticospinal tract and fine motor function after ICH. Moreover, results showed that 41% mitochondria were preferentially bundled to the acetylated α-tubulin in identifiable axons and dendrites in primary neurons. This impaired axonal transport of mitochondria in primary neurons of MEC17-/- mice. Given that opening of mitochondrial permeability transition pore (mPTP) induces mitochondrial dysfunction and impairs ATP supply thereby promoting axonal injury, we enhanced the availability of acetylated α-tubulin using TubA and inhibited mPTP opening with cyclosporin A. The results indicated that this combined treatment synergistically protected corticospinal tract integrity and promoted fine motor control recovery. These findings reveal key intracellular mechanisms that drive axonal degeneration after ICH and highlight the need to target multiple factors and respective regulatory mechanisms as an effective approach to prevent axonal degeneration and motor dysfunction after ICH.

Adeno-associated virus-mediated in vivo suppression of expression of EPHX2 gene modulates the activity of paraventricular nucleus neurons in spontaneously hypertensive rats.

BACKGROUND: Hypertension can be attributed to increased sympathetic activities. Presympathetic neurons in the paraventricular nucleus (PVN) of the hypothalamus are capable of modulating sympathetic outflow, thus contributing to the pathogenesis of neurogenic hypertension. Epoxyeicosatrienoic acids (EETs) were reported to have anti-hypertensive effects, which could be degraded by soluble epoxide hydrolase (sEH), encoded by EPHX2. However, the potential effect of EETs on PVN neuron activity and the underlying molecular mechanism are largely unknown. METHODS: Knockdown of EPHX2 in spontaneously hypertensive rats (SHRs) was achieved by tail-intravenous injection of AAV plasmid containing shRNA targeting EPHX2. Whole-cell patch clamp was used to record action potentials of PVN neurons. An LC-MS/MS System was employed to determine 14,15-EET levels in rat cerebrospinal fluid. qPCR and western blotting were applied to examine the expression level of EPHX2 in various tissues. ELISA and immunofluorescence staining were applied to examine the levels of ATP, D-serine and glial fibrillary acidic protein (GFAP) in isolated astrocytes. RESULTS: The expression level of EPHX2 was higher, while the level of 14,15-EET was lower in SHRs than normotensive Wistar-Kyoto rats (WKY) rats. The spike firing frequency of PNV neurons in SHRs was higher than in WKY rats at a given stimulus current, which could be reduced by either EPHX2 downregulation or 14,15-EET administration. In isolated hypothalamic astrocytes, the elevated intracellular ATP or D-serine induced by Angiotensin II (Ang II) treatment could be rescued by 14,15-EET addition or 14,15-EET combing serine racemase (SR) downregulation by siRNA, respectively. Furthermore, 14,15-EET treatment reduced the Ang II-induced elevation of GFAP immunofluorescence. CONCLUSIONS: The elevation of EET levels by EPHX2 downregulation reduced presympathetic neuronal activity in the PVN of SHRs, leading to a reduced sympathetic outflow in hypertension rats. The ATP/SR/D-serine pathway of astrocytes is involved in EET-mediated neuroprotection.

Chemo-Phototherapy with Carfilzomib-Encapsulated TiN Nanoshells Suppressing Tumor Growth and Lymphatic Metastasis.

The design of nanomedicine for cancer therapy, especially the treatment of tumor metastasis has received great attention. Proteasome inhibition is accepted as a new strategy for cancer therapy. Despite being a big breakthrough in multiple myeloma therapy, carfilzomib (CFZ), a second-in-class proteasome inhibitor is still unsatisfactory for solid tumor and metastasis therapy. In this study, hollow titanium nitride (TiN) nanoshells are synthesized as a drug carrier of CFZ. The TiN nanoshells have a high loading capacity of CFZ, and their intrinsic inhibitory effect on autophagy synergistically enhances the activity of CFZ. Due to an excellent photothermal conversion efficiency in the second near-infrared (NIR-II) region, TiN nanoshell-based photothermal therapy further induces a synergistic anticancer effect. In vivo study demonstrates that TiN nanoshells readily drain into the lymph nodes, which are responsible for tumor lymphatic metastasis. The CFZ-loaded TiN nanoshell-based chemo-photothermal therapy combined with surgery offers a remarkable therapeutic outcome in greatly inhibiting further metastatic spread of cancer cells. These findings suggest that TiN nanoshells act as an efficient carrier of CFZ for realizing enhanced outcomes for proteasome inhibitor-based cancer therapy, and this work also presents a "combined chemo-phototherapy assisted surgery" strategy, promising for future cancer treatment.

Oxidative stress-mediated up-regulation of ABC transporters in lung cancer cells.

This paper aimed to evaluate the role of oxidative stress in the regulation of ABC transporters in human lung cancer (A549) cells facing substrate (doxorubicin, DOX) and nonsubstrate (ethanol, ETH and hydrogen peroxide, HP) chemicals. After 24-h treatment, all the chemicals caused significant cytotoxicity as reflected by the reduction in cell viability and the increase in reactive oxygen species (ROS) levels. Depending on the rescuing effects of ROS scavenger including glutathione (GSH) and Vitamin C, the toxicity dependence on oxidative stress were found to be HP > ETH > DOX. The addition of transporter inhibitors significantly enhanced the ROS levels and death-inducing effects of chemicals, indicating the universal detoxification function of ABC transporters. At moderate ROS levels (about 3-4-folds of control levels, caused by 10 µM DOX, 400 mM ETH, and 400 µM HP), all the three chemicals induced the gene expressions and activities of ABC transporters, but these values decreased at too high ROS levels (8.36-folds of control levels) caused by HP at LC50 (800 µM). Such induction could be attenuated by GSH and KCZ, and was completely abolished by 50 µM KCZ, indicating an important role of oxidative stress and pregnane X receptor (PXR) in the induction of ABC transporters. Finally, this paper revealed the critical role of oxidative stress in the modulation of ABC transporters by either substrate or nonsubstrate chemicals during 24-h treatment. Such information should be beneficial for overcoming ABC transporter-mediated multidrug resistance.

Evaluation of the learning curve for conformal sphincter preservation operation in the treatment of ultralow rectal cancer.

BACKGROUND: To investigate the learning curve of conformal sphincter preservation operation (CSPO) in the treatment of ultralow rectal cancer and to further explore the influencing factors of operation time. METHODS: From August 2011 to April 2020, 108 consecutive patients with ultralow rectal cancer underwent CSPO by the same surgeon in the Department of Colorectal Surgery of Changhai Hospital. The moving average and cumulative sum control chart (CUSUM) curve were used to analyze the learning curve. The preoperative clinical baseline data, postoperative pathological data, postoperative complications, and survival data were compared before and after the completion of learning curve. The influencing factors of CSPO operation time were analyzed by univariate and multivariate analysis. RESULTS: According to the results of moving average and CUSUM method, CSPO learning curve was divided into learning period (1-45 cases) and learning completion period (46-108 cases). There was no significant difference in preoperative clinical baseline data, postoperative pathological data, postoperative complications, and survival data between the two stages. Compared with the learning period, the operation time (P < 0.05), blood loss (P < 0.05), postoperative flatus and defecation time (P < 0.05), liquid diet time (P < 0.05), and postoperative hospital stay (P < 0.05) in the learning completion period were significantly reduced, and the difference was statistically significant. Univariate and multivariate analysis showed that distance of tumor from anal verge (≥ 4cm vs. < 4cm, P = 0.039) and T stage (T3 vs. T1-2, P = 0.022) was independent risk factors for prolonging the operation time of CSPO. CONCLUSIONS: For surgeons with laparoscopic surgery experience, about 45 cases of CSPO are needed to cross the learning curve. At the initial stage of CSPO, beginners are recommended to select patients with ultralow rectal cancer whose distance of tumor from anal verge is less than 4 cm and tumor stage is less than T3 for practice, which can enable beginners to reduce the operation time, accumulate experience, build self-confidence, and shorten the learning curve on the premise of safety.