Novel Facets of the Liver Transcriptome Are Associated with the Susceptibility and Resistance to Lipid-Related Metabolic Disorders in Periparturient Holstein Cows

Lipid-related metabolic disorders (LRMD) are prevalent in early lactation dairy cows, and have detrimental effects on productivity and health. Our objectives were to identify cows resistant or susceptible to LRMD using a ketosis induction protocol (KIP) to discover differentially expressed liver genes and metabolic pathways associated with disposition. Clustering cows based on postpartum lipid metabolite concentrations within dietary treatments identified cows more or less susceptible (MS vs. LS) to LRMD within the control treatment, and more or less resistant (MR vs. LR) within the KIP treatment. Whole-transcriptome RNA sequencing was performed on liver samples (−28, +1, and +14 days relative to calving) to assess differential gene and pathway expression (LS vs. MS; MR vs. LR; n = 3 cows per cluster). Cows within the MS and LR clusters had evidence of greater blood serum β-hydroxybutyrate concentration and liver triglyceride content than the LS and MR clusters, respectively. The inferred metabolism of differentially expressed genes suggested a role of immune response (i.e., interferon-inducible proteins and major histocompatibility complex molecules). Additionally, unique roles for glutathione metabolism and eicosanoid metabolism in modulating susceptibility and resistance, respectively, were implicated. Overall, this research provides novel insight into the role of immunometabolism in LRMD pathology, and suggests the potential for unique control points for LRMD progression and severity.

Download Full-text

Bioinformatics Analysis and Validation of Differentially Expressed MicroRNAs with Their Target Genes Involved in GLP-1RA Facilitated Osteogenesis

Current Bioinformatics ◽

10.2174/1574893615999200508091615 ◽

2020 ◽

Vol 15 ◽

Author(s):

Na Wang ◽

Yukun Li ◽

Sijing Liu ◽

Liu Gao ◽

Chang Liu ◽

...

Keyword(s):

High Throughput Sequencing ◽

Target Genes ◽

Bioinformatics Analysis ◽

Differentially Expressed ◽

Functional Study ◽

Regulation Network ◽

Glucagon Like Peptide 1 ◽

G Protein Coupled ◽

Lower Expression

Background: Recent studies revealed that the hypoglycemic hormone, glucagon-like peptide-1 (GLP-1), acted as an important modulator in osteogenesis of bone marrow derived mesenchymal stem cells (BMSCs). Objectives: The aim of this study was to identify the specific microRNA (miRNA) using bioinformatics analysis and validate the presence of differentially expressed microRNAs with their target genes after GLP-1 receptor agonist (GLP-1RA) administration involved in ostogenesis of BMSCs. Methods: MiRNAs were extracted from BMSCs after 5 days’ treatment and sent for high-throughput sequencing for differentially expressed (DE) miRNAs analyses. Then the expression of the DE miRNAs verified by the real-time RT-PCR analyses. Target genes were predicted, and highly enriched GOs and KEGG pathway analysis were conducted using bioinformatics analysis. For the functional study, two of the target genes, SRY (sex determining region Y)-box 5 (SOX5) and G protein-coupled receptor 84 (GPR84), were identified. Results: A total of 5 miRNAs (miRNA-509-5p, miRNA-547-3p, miRNA-201-3p, miRNA-201-5p, and miRNA-novel-272-mature) were identified differentially expressed among groups. The expression of miRNA-novel-272-mature were decreased during the osteogenic differentiation of BMSCs, and GLP-1RA further decreased its expression. MiRNA-novel-272-mature might interact with its target mRNAs to enhance osteogenesis. The lower expression of miRNA-novel-272-mature led to an increase in SOX5 and a decrease in GPR84 mRNA expression, respectively. Conclusions: Taken together, these results provide further insights to the pharmacological properties of GLP-1RA and expand our knowledge on the role of miRNAs-mRNAs regulation network in BMSCs’ differentiation.

Download Full-text

Neuronal nitric oxide synthase and systemic vasodilation in rats with cirrhosis

AJP Renal Physiology ◽

10.1152/ajprenal.2000.279.6.f1110 ◽

2000 ◽

Vol 279 (6) ◽

pp. F1110-F1115 ◽

Cited By ~ 50

Author(s):

Lieming Xu ◽

Ethan P. Carter ◽

Mamiko Ohara ◽

Pierre-Yves Martin ◽

Boris Rogachev ◽

...

Keyword(s):

Nitric Oxide ◽

Liver Cirrhosis ◽

Nitric Oxide Synthase ◽

Control Treatment ◽

Sodium Balance ◽

Hyperdynamic Circulation ◽

Molecular Approaches ◽

Advanced Liver Cirrhosis ◽

Oxide Synthase

Cirrhosis is typically associated with a hyperdynamic circulation consisting of low blood pressure, low systemic vascular resistance (SVR), and high cardiac output. We have recently reported that nonspecific inhibition of nitric oxide synthase (NOS) with nitro-l-arginine methyl ester reverses the hyperdynamic circulation in rats with advanced liver cirrhosis induced by carbon tetrachloride (CCl4). Although an important role for endothelial NOS (eNOS) is documented in cirrhosis, the role of neuronal NOS (nNOS) has not been investigated. The present study was carried out to specifically investigate the role of nNOS during liver cirrhosis. Specifically, physiological, biochemical, and molecular approaches were employed to evaluate the contribution of nNOS to the cirrhosis-related hyperdynamic circulation in CCl4-induced cirrhotic rats with ascites. Cirrhotic animals had a significant increase in water and sodium retention. In the aorta from cirrhotic animals, both nNOS protein expression and cGMP concentration were significantly elevated compared with control. Treatment of cirrhotic rats for 7 days with the specific nNOS inhibitor 7-nitroindazole (7-NI) normalized the low SVR and mean arterial pressure, elevated cardiac index, and reversed the positive sodium balance. Increased plasma arginine vasopressin concentrations in the cirrhotic animals were also repressed with 7-NI in association with diminished water retention. The circulatory changes were associated with a reduction in aortic nNOS expression and cGMP. However, 7-NI treatment did not restore renal function in cirrhotic rats (creatinine clearance: 0.76 ± 0.03 ml · min−1· 100 g body wt−1in cirrhotic rats vs. 0.79 ± 0.05 ml · min−1· 100 g body wt−1in cirrhotic rats+7-NI; P NS.). Taken together, these results indicate that nNOS-derived NO contributes to the development of the hyperdynamic circulation and fluid retention in cirrhosis.

Download Full-text

Adipose Tissue Immunomodulation and Treg/Th17 Imbalance in the Impaired Glucose Metabolism of Children with Obesity

Children ◽

10.3390/children8070554 ◽

2021 ◽

Vol 8 (7) ◽

pp. 554

Author(s):

Stefania Croce ◽

Maria Antonietta Avanzini ◽

Corrado Regalbuto ◽

Erika Cordaro ◽

Federica Vinci ◽

...

Keyword(s):

Adipose Tissue ◽

Glucose Metabolism ◽

Th17 Cells ◽

Metabolic Disorders ◽

Potential Role ◽

Immune Monitoring ◽

Metabolic Dysfunction ◽

Impaired Glucose Metabolism ◽

T Cell Infiltration

In the last few decades, obesity has increased dramatically in pediatric patients. Obesity is a chronic disease correlated with systemic inflammation, characterized by the presence of CD4 and CD8 T cell infiltration and modified immune response, which contributes to the development of obesity related diseases and metabolic disorders, including impaired glucose metabolism. In particular, Treg and Th17 cells are dynamically balanced under healthy conditions, but imbalance occurs in inflammatory and pathological states, such as obesity. Some studies demonstrated that peripheral Treg and Th17 cells exhibit increased imbalance with worsening of glucose metabolic dysfunction, already in children with obesity. In this review, we considered the role of adipose tissue immunomodulation and the potential role played by Treg/T17 imbalance on the impaired glucose metabolism in pediatric obesity. In the patient care, immune monitoring could play an important role to define preventive strategies of pediatric metabolic disease treatments.

Download Full-text

Genome-Wide Identification and Characterization of Long Noncoding RNAs Involved in Chinese Wheat Mosaic Virus Infection of Nicotiana benthamiana

Biology ◽

10.3390/biology10030232 ◽

2021 ◽

Vol 10 (3) ◽

pp. 232

Author(s):

Weiran Zheng ◽

Haichao Hu ◽

Qisen Lu ◽

Peng Jin ◽

Linna Cai ◽

...

Keyword(s):

Virus Infection ◽

Mosaic Virus ◽

Nicotiana Benthamiana ◽

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Differentially Expressed ◽

Genome Wide ◽

Chinese Wheat

Recent studies have shown that a large number of long noncoding RNAs (lncRNAs) can regulate various biological processes in animals and plants. Although lncRNAs have been identified in many plants, they have not been reported in the model plant Nicotiana benthamiana. Particularly, the role of lncRNAs in plant virus infection remains unknown. In this study, we identified lncRNAs in N. benthamiana response to Chinese wheat mosaic virus (CWMV) infection by RNA sequencing. A total of 1175 lncRNAs, including 65 differentially expressed lncRNAs, were identified during CWMV infection. We then analyzed the functions of some of these differentially expressed lncRNAs. Interestingly, one differentially expressed lncRNA, XLOC_006393, was found to participate in CWMV infection as a precursor to microRNAs in N. benthamiana. These results suggest that lncRNAs play an important role in the regulatory network of N. benthamiana in response to CWMV infection.

Download Full-text

Suppression of personality variation in boldness during foraging in three-spined sticklebacks

Behavioral Ecology and Sociobiology ◽

10.1007/s00265-021-03007-2 ◽

2021 ◽

Vol 75 (4) ◽

Author(s):

Hannah E. A. MacGregor ◽

Aislinn Cottage ◽

Christos C. Ioannou

Keyword(s):

Negative Feedback ◽

Risk Taking ◽

Positive Feedback ◽

Gasterosteus Aculeatus ◽

Control Treatment ◽

Refuge Use ◽

Individual Level ◽

Behavioural Type ◽

State Behaviour

Abstract Consistent inter-individual variation in behaviour within a population, widely referred to as personality variation, can be affected by environmental context. Feedbacks between an individual’s behaviour and state can strengthen (positive feedback) or weaken (negative feedback) individual differences when experiences such as predator encounters or winning contests are dependent on behavioural type. We examined the influence of foraging on individual-level consistency in refuge use (a measure of risk-taking, i.e. boldness) in three-spined sticklebacks, Gasterosteus aculeatus, and particularly whether changes in refuge use depended on boldness measured under control conditions. In the control treatment trials with no food, individuals were repeatable in refuge use across repeated trials, and this behavioural consistency did not differ between the start and end of these trials. In contrast, when food was available, individuals showed a higher degree of consistency in refuge use at the start of the trials versus controls but this consistency significantly reduced by the end of the trials. The effect of the opportunity to forage was dependent on behavioural type, with bolder fish varying more in their refuge use between the start and the end of the feeding trials than shyer fish, and boldness positively predicted the likelihood of feeding at the start but not at the end of the trials. This suggests a state-behaviour feedback, but there was no overall trend in how bolder individuals changed their behaviour. Our study shows that personality variation can be suppressed in foraging contexts and a potential but unpredictable role of feedbacks between state and behaviour. Significance statement In this experimental study, we examined how foraging influences consistency in risk-taking in individual three-spined sticklebacks. We show that bolder individuals become less consistent in their risk-taking behaviour than shyer individuals during foraging. Some bolder individuals reinforce their risk-taking behaviour, suggesting a positive feedback between state and behaviour, while others converge on the behaviour of shyer individuals, suggesting a negative feedback. In support of a role of satiation in driving negative feedback effects, we found that bolder individuals were more likely to feed at the start but not at the end of the trials. Overall, our findings suggest that foraging can influence personality variation in risk-taking behaviour; however, the role of feedbacks may be unpredictable.

Download Full-text

Inhibition of histone methyltransferase G9a attenuates liver cancer initiation by sensitizing DNA-damaged hepatocytes to p53-induced apoptosis

Cell Death and Disease ◽

10.1038/s41419-020-03381-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Takuma Nakatsuka ◽

Keisuke Tateishi ◽

Hiroyuki Kato ◽

Hiroaki Fujiwara ◽

Keisuke Yamamoto ◽

...

Keyword(s):

Dna Damage ◽

Epigenetic Modification ◽

Histone Methyltransferase ◽

Preventive Strategy ◽

Tumor Initiation ◽

Liver Transcriptome ◽

Genetic Abnormalities ◽

Responsive Element ◽

Induced Apoptosis

AbstractWhile the significance of acquired genetic abnormalities in the initiation of hepatocellular carcinoma (HCC) has been established, the role of epigenetic modification remains unknown. Here we identified the pivotal role of histone methyltransferase G9a in the DNA damage-triggered initiation of HCC. Using liver-specific G9a-deficient (G9aΔHep) mice, we revealed that loss of G9a significantly attenuated liver tumor initiation caused by diethylnitrosamine (DEN). In addition, pharmacological inhibition of G9a attenuated the DEN-induced initiation of HCC. After treatment with DEN, while the induction of γH2AX and p53 were comparable in the G9aΔHep and wild-type livers, more apoptotic hepatocytes were detected in the G9aΔHep liver. Transcriptome analysis identified Bcl-G, a pro-apoptotic Bcl-2 family member, to be markedly upregulated in the G9aΔHep liver. In human cultured hepatoma cells, a G9a inhibitor, UNC0638, upregulated BCL-G expression and enhanced the apoptotic response after treatment with hydrogen peroxide or irradiation, suggesting an essential role of the G9a-Bcl-G axis in DNA damage response in hepatocytes. The proposed mechanism was that DNA damage stimuli recruited G9a to the p53-responsive element of the Bcl-G gene, resulting in the impaired enrichment of p53 to the region and the attenuation of Bcl-G expression. G9a deletion allowed the recruitment of p53 and upregulated Bcl-G expression. These results demonstrate that G9a allows DNA-damaged hepatocytes to escape p53-induced apoptosis by silencing Bcl-G, which may contribute to the tumor initiation. Therefore, G9a inhibition can be a novel preventive strategy for HCC.

Download Full-text

Tocopherols and Tocotrienols—Bioactive Dietary Compounds; What Is Certain, What Is Doubt?

International Journal of Molecular Sciences ◽

10.3390/ijms22126222 ◽

2021 ◽

Vol 22 (12) ◽

pp. 6222

Author(s):

Kacper Szewczyk ◽

Aleksandra Chojnacka ◽

Magdalena Górnicka

Keyword(s):

Vitamin E ◽

Metabolic Disorders ◽

Tissue Concentration ◽

Biological Properties ◽

Biological Role ◽

Future Research ◽

The Past ◽

The Subject ◽

The Relationship

Tocopherols and tocotrienols are natural compounds of plant origin, available in the nature. They are supplied in various amounts in a diet, mainly from vegetable oils, some oilseeds, and nuts. The main forms in the diet are α- and γ-tocopherol, due to the highest content in food products. Nevertheless, α-tocopherol is the main form of vitamin E with the highest tissue concentration. The α- forms of both tocopherols and tocotrienols are considered as the most metabolically active. Currently, research results indicate also a greater antioxidant potential of tocotrienols than tocopherols. Moreover, the biological role of vitamin E metabolites have received increasing interest. The aim of this review is to update the knowledge of tocopherol and tocotrienol bioactivity, with a particular focus on their bioavailability, distribution, and metabolism determinants in humans. Almost one hundred years after the start of research on α-tocopherol, its biological properties are still under investigation. For several decades, researchers’ interest in the biological importance of other forms of vitamin E has also been growing. Some of the functions, for instance the antioxidant functions of α- and γ-tocopherols, have been confirmed in humans, while others, such as the relationship with metabolic disorders, are still under investigation. Some studies, which analyzed the biological role and mechanisms of tocopherols and tocotrienols over the past few years described new and even unexpected cellular and molecular properties that will be the subject of future research.

Download Full-text

Optical Characterization of Alternaria spp. Contaminated Wheat Grain and Its Influence in Early Broilers Nutrition on Oxidative Stress

Sustainability ◽

10.3390/su13074005 ◽

2021 ◽

Vol 13 (7) ◽

pp. 4005

Author(s):

Nikola Puvača ◽

Snežana Tanasković ◽

Vojislava Bursić ◽

Aleksandra Petrović ◽

Jordan Merkuri ◽

...

Keyword(s):

Oxidative Stress ◽

Body Weight ◽

Broiler Chickens ◽

Basal Diet ◽

Feed Consumption ◽

Control Treatment ◽

Second Phase ◽

Wheat Grain ◽

Color Properties ◽

Dietary Treatments

The aim of this research was the visual characterization and investigating the effects of Alternaria spp. contaminated wheat grains in the starter stage of broilers nutrition on productive parameters and oxidative stress. The research was divided into two phases. Bunches of wheat in post-harvest period of year 2020 was collected from a various locality in Serbia and Albania. In the first phase, collected samples were visual characterized by Alternaria spp. presence by color measurement methods. Gained results are conferred in the range of the color properties of grain color properties of Alternaria toxins. Wheat grain samples were significantly different (p < 0.05) in terms of all measured color parameters (L*, a*, b*). Classification of field fungi in analyzed wheat grain samples showed that the significant field fungi were Rhizopus spp., followed by Alternaria spp., and Fusarium spp. In the second phase, biological tests with chickens were carried out during the broiler chickens’ dietary starter period in the first 14th days of age. At the beginning of the experiment, a total of 180-day-old Ross 308 strain broilers were equally distributed into three dietary treatments, with four replicates each. Dietary treatments in the experiments were as follows: basal diet without visual contamination of Alternaria spp. with 25% wheat (A1), a basal diet with visual contamination of Alternaria spp. with 25% wheat from Serbia (A2), basal diet with visual contamination of Alternaria spp. with 25% wheat from Albania (A3). The trial with chickens lasted for 14 days. After the first experimental week, wheat infected with Alternaria spp. in treatment A2 and A3 expressed adverse effects. The highest body weight of chickens of 140.40 g was recorded in broilers on control treatment A1 with statistically significant differences (p < 0.05) compared to treatments A2 (137.32 g) and A3 (135.35 g). At the end of the second week of test period, a statistically significant (p < 0.05) difference in body weight of broiler chickens could be noticed. The highest body weight of 352.68 g was recorded in control treatment A1, with statistically significant differences compared to other Alternaria spp. treatments. The lowest body weight of chickens was recorded in treatment A3 (335.93 g). Results of feed consumption and feed conversion ratio showed some numerical differences between treatments but without any statistically significant differences (p > 0.05). Alternaria spp. contaminated diet increased glutathione (GSH), glutathione reductase (GR), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) and decreased peroxidase (POD) and superoxide dismutase (SOD) serum levels, respectively. Built on the achieved results, it can be concluded that the wheat contaminated with Alternaria spp. in broilers nutrition negatively affected growth, decreased oxidative protection and interrupted chicken welfare in the first period of life.

Download Full-text

The Role of High Fat Diets and Liver Peptidase Activity in the Development of Obesity and Insulin Resistance in Wistar Rats

Nutrients ◽

10.3390/nu12030636 ◽

2020 ◽

Vol 12 (3) ◽

pp. 636

Author(s):

Germán Domínguez-Vías ◽

Ana Belén Segarra ◽

Manuel Ramírez-Sánchez ◽

Isabel Prieto

Keyword(s):

Glucose Metabolism ◽

Wistar Rats ◽

Metabolic Disorders ◽

Peptidase Activity ◽

High Fat ◽

Β Cell ◽

High Fat Diets ◽

Glutamyl Transferase ◽

Fat Diets

High-fat diets (HFD) have been widely associated with an increased risk of metabolic disorders and overweight. However, a high intake of sources that are rich in monounsaturated fatty acids has been suggested as a dietary agent that is able to positively influence energy metabolism and vascular function. The main objective of this study was to analyze the role of dietary fats on hepatic peptidases activities and metabolic disorders. Three diets: standard (S), HFD supplemented with virgin olive oil (VOO), and HFD supplemented with butter plus cholesterol (Bch), were administered over six months to male Wistar rats. Plasma and liver samples were collected for clinical biochemistry and aminopeptidase activities (AP) analysis. The expression of inducible nitric oxide synthase (iNOS) was also determined by Western blot in liver samples. The diet supplement with VOO did not induce obesity, in contrast to the Bch group. Though the VOO diet increased the time that was needed to return to the basal levels of plasma glucose, the fasting insulin/glucose ratio and HOMA2-%B index (a homeostasis model index of insulin secretion and valuation of β-cell usefulness (% β-cell secretion)) were improved. An increase of hepatic membrane-bound dipeptidyl-peptidase 4 (DPP4) activity was found only in VOO rats, even if no differences in fasting plasma glucagon-like peptide 1 (GLP-1) were obtained. Both HFDs induced changes in hepatic pyroglutamyl-AP in the soluble fraction, but only the Bch diet increased the soluble tyrosyl-AP. Angiotensinase activities that are implicated in the metabolism of angiotensin II (AngII) to AngIV increased in the VOO diet, which was in agreement with the higher activity of insulin-regulated-AP (IRAP) in this group. Otherwise, the diet that was enriched with butter increased soluble gamma-glutamyl transferase (GGT) and Leucyl-AP, iNOS expression in the liver, and plasma NO. In summary, VOO increased the hepatic activity of AP that were related to glucose metabolism (DPP4, angiotensinases, and IRAP). However, the Bch diet increased activities that are implicated in the control of food intake (Tyrosine-AP), the index of hepatic damage (Leucine-AP and GGT), and the expression of hepatic iNOS and plasma NO. Taken together, these results support that the source of fat in the diet affects several peptidases activities in the liver, which could be related to alterations in feeding behavior and glucose metabolism.

Download Full-text