Myocardial Rev-erb-Mediated Diurnal Metabolic Rhythm and Obesity Paradox.

BACKGROUND: The nuclear receptor Rev-erbα/ß, a key component of the circadian clock, emerges as a drug target for heart diseases, but the function of cardiac Rev-erb has not been studied in vivo. Circadian disruption is implicated in heart diseases, but it is unknown whether cardiac molecular clock dysfunction is associated with the progression of any naturally occurring human heart diseases. Obesity paradox refers to the seemingly protective role of obesity for heart failure, but the mechanism is unclear. METHODS: We generated mouse lines with cardiac-specific Rev-erbα/ß knockout (KO), characterized cardiac phenotype, conducted multi-omics (RNA-sequencing, chromatin immunoprecipitation sequencing, proteomics, and metabolomics) analyses, and performed dietary and pharmacological rescue experiments to assess the time-of-the-day effects. We compared the temporal pattern of cardiac clock gene expression with the cardiac dilation severity in failing human hearts. RESULTS: KO mice display progressive dilated cardiomyopathy and lethal heart failure. Inducible ablation of Rev-erbα/ß in adult hearts causes similar phenotypes. Impaired fatty acid oxidation in the KO myocardium, in particular, in the light cycle, precedes contractile dysfunctions with a reciprocal overreliance on carbohydrate utilization, in particular, in the dark cycle. Increasing dietary lipid or sugar supply in the dark cycle does not affect cardiac dysfunctions in KO mice. However, obesity coupled with systemic insulin resistance paradoxically ameliorates cardiac dysfunctions in KO mice, associated with rescued expression of lipid oxidation genes only in the light cycle in phase with increased fatty acid availability from adipose lipolysis. Inhibition of glycolysis in the light cycle and lipid oxidation in the dark cycle, but not vice versa, ameliorate cardiac dysfunctions in KO mice. Altered temporal patterns of cardiac Rev-erb gene expression correlate with the cardiac dilation severity in human hearts with dilated cardiomyopathy. CONCLUSIONS: The study delineates temporal coordination between clock-mediated anticipation and nutrient-induced response in myocardial metabolism at multi-omics levels. The obesity paradox is attributable to increased cardiac lipid supply from adipose lipolysis in the fasting cycle due to systemic insulin resistance and adiposity. Cardiac molecular chronotypes may be involved in human dilated cardiomyopathy. Myocardial bioenergetics downstream of Rev-erb may be a chronotherapy target in treating heart failure and dilated cardiomyopathy.

Isorhamnetin inhibits inflammatory response to alleviate DHEA-induced polycystic ovary syndrome in rats.

OBJECTIVE: To explore the role of isorhamnetin on polycystic ovary syndrome (PCOS) in rats. METHODS: Sprague Dawley (SD) rats were subcutaneously injected with dehydroepiandrosteron (DHEA) to establish PCOS model. Hematoxylin and eosin (H&E) staining and TdT-mediated dUTP Nick-End Labeling (TUNEL) were used to measure histological changes and apoptosis of ovary tissues. The levels of serum hormones and inflammatory factors in ovary tissues were measured by enzyme-linked immuno sorbent assay (ELISA). RESULTS: In DHEA-induced PCOS rats, the levels of serum glucose, insulin, testosterone and luteinizing hormone (LH) were enhanced, estradiol (E2), sex hormone-binding globulin (SHBG), follicle stimulating hormone (FSH) levels were decreased, inflammatory levels and apoptosis of ovary tissues were increased. Additionally, DHEA increased the body weight, ovary weight, and ovary volume, cystic follicles, and decreased corpus luteum. Moreover, the tumor necrosis factor (TNF) signaling pathway was activated in PCOS rats. The levels of TNF receptor superfamily member 1 A (TNFR1), TNF-α, and fas cell surface death feceptor (FAS) were enhanced in ovary tissues of DHEA induced PCOS rats. Isorhamnetin (ISO) treatment after DHEA modeling markedly reduced serum levels of glucose, insulin, testosterone and LH, increased E2, SHBG, FSH level, decreased inflammatory levels, and inhibited apoptosis and decreased body weight, ovary weight, and ovary volume. The levels of TNFR1, TNF-α, and FAS were markedly decreased after ISO treatment in PCOS rats. Additionally, ISO alone had no significant effect on rats. CONCLUSION: Isorhamnetin inhibits inflammatory response to alleviate DHEA-induced PCOS in rats by inactivating the TNF signaling pathway.

HDAC3 controls male fertility through enzyme-independent transcriptional regulation at the meiotic exit of spermatogenesis.

The transition from meiotic spermatocytes to postmeiotic haploid germ cells constitutes an essential step in spermatogenesis. The epigenomic regulatory mechanisms underlying this transition remain unclear. Here, we find a prominent transcriptomic switch from the late spermatocytes to the early round spermatids during the meiotic-to-postmeiotic transition, which is associated with robust histone acetylation changes across the genome. Among histone deacetylases (HDACs) and acetyltransferases, we find that HDAC3 is selectively expressed in the late meiotic and early haploid stages. Three independent mouse lines with the testis-specific knockout of HDAC3 show infertility and defects in meiotic exit with an arrest at the late stage of meiosis or early stage of round spermatids. Stage-specific RNA-seq and histone acetylation ChIP-seq analyses reveal that HDAC3 represses meiotic/spermatogonial genes and activates postmeiotic haploid gene programs during meiotic exit, with associated histone acetylation alterations. Unexpectedly, abolishing HDAC3 catalytic activity by missense mutations in the nuclear receptor corepressor (NCOR or SMRT) does not cause infertility, despite causing histone hyperacetylation as HDAC3 knockout, demonstrating that HDAC3 enzyme activity is not required for spermatogenesis. Motif analysis of the HDAC3 cistrome in the testes identified SOX30, which has a similar spatiotemporal expression pattern as HDAC3 during spermatogenesis. Depletion of SOX30 in the testes abolishes the genomic recruitment of the HDAC3 to the binding sites. Collectively, these results establish the SOX30/HDAC3 signaling as a key regulator of the transcriptional program in a deacetylase-independent manner during the meiotic-to-postmeiotic transition in spermatogenesis.

Butylparaben weakens female fertility via causing oocyte meiotic arrest and fertilization failure in mice.

Butylparaben is an ubiquitous environmental endocrine disruptor, that is commonly used in cosmetics and personal care product due to its anti-microbial properties. Butylparaben has been shown to cause developmental toxicity, endocrine and metabolic disorders and immune diseases. However, little is known about the impact on female fertility, especially oocyte quality. In the present study, we reported that butylparaben influenced female fertility by showing the disturbed oocyte meiotic capacity and fertilization potential. Specifically, butylparaben results in the oocyte maturation arrest by impairing spindle/chromosome structure and microtubule stability. Besides, butylparaben results in fertilization failure by impairing the dynamics of Juno and ovastacin and the sperm binding ability. Last, single-cell transcriptome analysis showed that butylparaben-induced oocyte deterioration was caused by mitochondrial dysfunction, which led to the accumulation of ROS and occurrence of apoptosis. Collectively, our study indicates that mitochondrial dysfunction and redox perturbation is the major cause of the weakened female fertility expoesd to butylparaben.

Transcriptome profiling of hepatic and renal mRNAs and lncRNAs under a nutritional restriction during pregnancy in a sheep model.

This study aimed to investigate the transcriptome profiles of liver and kidney in pregnant sheep under a nutritional restriction. Twenty Hu sheep were segregated into control group (CON) and severe feed restriction (FR) group. Results showed that the concentration of insulin decreased, whereas glucagon, epinephrine, and norepinephrine increased in the FR group. Histological morphology showed no apparent difference in terms of fat deposition in the kidney. In addition, FR significantly decreased the hepatic gene expression of gluconeogenic genes. However, in the kidney, the relative mRNA expression levels of gluconeogenic genes and glucose transporter 1 were observed to increase while the mRNA expression of sodium-glucose co-transporter 1 were decreased by FR. The differentially expressed genes in the liver were associated with fatty acid metabolism and inflammation. In the kidney, FR mainly activated the gluconeogenesis improving negative energy balance. These results provide a better understanding of the consequences of starvation during pregnancy.

Undernutrition-induced lipid metabolism disorder triggers oxidative stress in maternal and fetal livers using a model of pregnant sheep.

This study aimed to evaluate the oxidative status and antioxidant capacity in maternal and fetal livers upon undernutrition as well as the connection between oxidative stress and lipid metabolism disorder. Ten ewes, who were pregnant for 115 days, were restricted to a 30% level of ad libitum feed intake to develop an undernourished model, while another 10 pregnant ewes were fed normally as controls. Undernutrition induced severe lipid metabolism disorder and oxidative stress in blood, maternal liver, and fetal liver. RNA-sequencing data displayed that antioxidant capacity was changed and antioxidant genes were downregulated in maternal and fetal livers of the undernourished model. Non-esterified fatty acids (NEFAs) and beta-hydroxybutyrate (BHBA) levels showed a positive correlation with oxidative indices and negative correlation with the expression of antioxidant genes both in maternal and fetal livers. Primary hepatocytes experiments confirmed that both high levels of NEFAs and BHBA could elicit oxidative stress and decrease antioxidant capacity, and the peroxisome proliferator-activated receptor alpha (PPARA)/retinoid X receptor alpha (RXRA) signaling pathway played a vital role in enhancing antioxidant capacity and relieving oxidative stress. In conclusion, maternal undernutrition induced lipid metabolism disorder, which downregulated antioxidant genes, decreased antioxidant activity, and further triggered oxidative stress both in maternal and fetal livers. Activation of PPARA/RXRA signaling could enhance antioxidant capacity and mitigate oxidative stress. Our findings contribute to protecting the pregnant mother and her fetus from oxidative stress.

Maternal undernutrition induces fetal hepatic lipid metabolism disorder and affects the development of fetal liver in a sheep model.

Undernutrition accelerates body fat mobilization to alleviate negative energy balance, which disrupts homeostasis of lipid metabolism in maternal liver. However, little is known about its effect on fetal metabolism and development. Here, a sheep model was used to explore whether maternal undernutrition induces fetal lipid metabolism disorder and further inhibits fetal hepatic development. Twenty pregnant ewes were either fed normally or restricted to 30% level for 15 d, after which fetal hepatic samples were collected to conduct transcriptome, metabolome, histomorphology, and biochemical analysis. Results showed that maternal undernutrition altered the general transcriptome profile and metabolic mode in fetal liver. Fatty acid oxidation and ketogenesis were enhanced in fetal livers of undernourished ewes, which might be promoted by the activated peroxisome proliferator-activated receptor α signaling pathway, whereas cholesterol, steroid, and fatty acid synthesis were repressed. Maternal undernutrition increased triglyceride synthesis, decreased triglyceride degradation, and inhibited phospholipid degradation and synthesis in fetal liver. In addition, our data revealed that maternal undernutrition extremely inhibited DNA replication, cell cycle progression, and antiapoptosis and broke the balance between cell proliferation and apoptosis in fetal liver, indicating that maternal undernutrition affects the growth and development of fetal liver. Generally, these findings provide evidence that maternal undernutrition during pregnancy disturbs fetal lipid metabolism and inhibits fetal hepatic development in sheep, which greatly contribute to the further study of fetal metabolism and development in human beings.-Xue, Y., Guo, C., Hu, F., Zhu, W., Mao, S. Maternal undernutrition induces fetal hepatic lipid metabolism disorder and affects the development of fetal liver in a sheep model.

Urine metabolome alterations in malnutrition and the impact of glycerol or rumen-protected choline chloride supplementation in advanced pregnant ewes.

The objective of this study was to explore the metabolic profiles of pregnancy malnutrition induced by feed restriction (FR) and the counteracting effects of glycerol and rumen-protected choline chloride supplementation. Two feeding trials were conducted. In the first experiment, twenty pregnant Hu sheep carrying multiple fetuses with a gestation period of 108 d were randomly divided into two groups. The ewes in the control (CON) group were offered 100 % of their nutritional requirements as recommended by the National Research Council (NRC), while the FR group was offered 30 % of feed intake of CON for 15 d. In the second experiment, eighteen pregnant Hu sheep were offered a feed intake comprising 30 % of the NRC-recommended nutritional requirements twice daily. The sheep were randomly divided into three groups: the FR group in the second experiment (FR2), with no supplementation, the glycerol (GLY) group, which received 40 ml of glycerol per d, and the rumen-protected choline chloride (RPC) group, which received 10 g of rumen-protected choline chloride per d for 9 d. In the first experiment, the urine metabolome of sixteen ewes showed significant difference between the CON group and FR group. Compared with the CON group, FR decreased the level of d-glucose, lactic acid, levoglucosan, α-ketoglutarate, phosphohydroxypyruvic acid, glucose 6-phosphate and the methyl donors, while increasing the level of pyruvate, fumaric acid and carnitines in urine. Both the GLY and RPC treatments counteracted some of these changes and modulated the urine metabolome in advanced pregnant ewes suffering from malnutrition.

Undernutrition shifted colonic fermentation and digest-associated bacterial communities in pregnant ewes.

The objective of this study was to evaluate the effect of undernutrition on colonic microbiota and fermentation in pregnant ewes. Sixteen ewes bearing multiple fetuses for 115 days in the control (CON) and severe feed restriction (SFR) groups were fed 100% and 30% level of ad libitum feed intake, respectively. After 15-day treatment, all ewes were sacrificed to collect colonic digesta samples to extract DNA for 16S rRNA sequencing and to detect fermentation parameters. Our data showed that SFR increased (P < 0.05) the levels of colonic propionate, isobutyrate, butyrate, isovalerate, and valerate, and slightly decreased (P < 0.1) colonic pH. The mole proportions of isobutyrate, butyrate, and isovalerate were increased (P < 0.05) upon SFR while that of acetate was decreased (P < 0.05). Hematoxylin-eosin staining sections exhibited the disorderly, irregular, and loose arrangement and part sloughing of colonic epithelial cells. Furthermore, SFR decreased (P < 0.05) the diversity of colonic microbiota and changed the microbial communities. At the genus level, SFR increased (P < 0.05) the abundance of unclassified Peptococcaceae and decreased (P < 0.05) the abundances of Ruminococcus, unclassified Ruminococcaceae, and unclassified VadinBB60. Additionally, the abundances of Ruminococcus and unclassified Ruminococcaceae were positively correlated (P < 0.05) with the acetate proportion while the abundance of unclassified Peptococcaceae was negatively correlated (P < 0.05) with the percentages of isobutyrate, butyrate, and isovalerate. In summary, SFR diminished the diversity of bacteria, affected the composition of bacterial communities, and finally changed the colonic fermentation pattern and epithelial histomorphology in pregnant ewes. KEY POINTS: • Undernutrition changed colonic bacterial diversity and composition in pregnant ewes. • Microbial alteration affected colonic fermentation pattern and parameters. • Alteration of colonic microbiota and fermentation damaged epithelium histomorphology. Graphical abstract.

Non-monotonic dose-response effects of arsenic on glucose metabolism.

BACKGROUND: Inorganic arsenic (iAs) is a widespread environmental toxin. In addition to being a human carcinogen, its effect on diabetes has started to gain recognition recently. Insulin is the key hormone regulating systemic glucose metabolism. The in vivo effect of iAs on insulin sensitivity has not been directly addressed. OBJECTIVES: Here we use mouse models to dissect the dose-dependent effects of iAs on glucose metabolism in vivo. METHODS: We performed hyperinsulinemic-euglycemic clamp, the gold standard analysis of systemic insulin sensitivity. We also performed dynamic metabolic testings and RNA-seq analysis. RESULTS: We found that a low-dose exposure (0.25 ppm iAs in drinking water) caused glucose intolerance in adult male C57BL/6 mice, likely by disrupting glucose-induced insulin secretion without affecting peripheral insulin sensitivity. However, a higher-dose exposure (2.5 ppm iAs) had diminished effects on glucose tolerance despite disrupted pancreatic insulin secretion. Insulin Clamp analysis showed that 2.5 ppm iAs actually enhanced systemic insulin sensitivity by simultaneously enhancing insulin-stimulated glucose uptake in skeletal muscles and improved insulin-mediated suppression of endogenous glucose production. RNA-seq analysis of skeletal muscles revealed that 2.5 ppm iAs regulated expression of many genes involved in the metabolism of fatty acids, pyruvate, and amino acids. CONCLUSION: These findings suggest that iAs has opposite glycemic effects on distinct metabolic tissues at different dose thresholds. Such non-monotonic dose-response effects of iAs on glucose tolerance shed light on the complex interactions between iAs and the systemic glucose metabolism, which could potentially help reconcile some of the conflicting results in human epidemiological studies.

Thymol Mitigates Cadmium Stress by Regulating Glutathione Levels and Reactive Oxygen Species Homeostasis in Tobacco Seedlings.

Thymol is a famous plant-derived compound that has been widely used in pharmacy due to its antioxidant and antimicrobial properties. However, the modulation of intrinsic plant physiology by thymol remains unclear. It is a significant challenge to confer plant tolerance to Cd (cadmium) stress. In the present study physiological, histochemical, and biochemical methods were applied to investigate thymol-induced Cd tolerance in tobacco (Nicotiana tabacum) seedlings. Thymol was able to alleviate Cd-induced growth inhibition of tobacco seedlings in both dose- and time-dependent manners. Both histochemical detection and in-tube assays suggested that thymol treatment blocked Cd-induced over-generation of reactive oxygen species (ROS), lipid peroxidation, and loss of membrane integrity in both leaves and roots. Thymol decreased Cd-induced cell death that was indicated in vivo by propidium iodide (PI) and trypan blue, respectively. Thymol stimulated glutathione (GSH) biosynthesis by upregulating the expression of γ-glutamylcysteine synthetase 1 (GSH1) in Cd-treated seedlings, which may contribute to the alleviation of Cd-induced oxidative injury. In situ fluorescent detection of intracellular Cd2+ revealed that thymol significantly decreased free Cd2+ in roots, which could be explained by the thymol-stimulated GSH biosynthesis and upregulation of the expression of phyochelatin synthase 1 (PCS1). Taken together, these results suggested that thymol has great potential to trigger plant resistant responses to combat heavy metal toxicity, which may help our understanding of the mechanism for thymol-modulated cell metabolic pathways in response to environmental stimuli.

Cinnamaldehyde Ameliorates Cadmium-Inhibited Root Elongation in Tobacco Seedlings via Decreasing Endogenous Hydrogen Sulfide Production.

Cinnamaldehyde (CA) is natural plant-derived compound that has been highly appreciated for its medicinal properties. However, little information is known about the regulation of plant intrinsic physiology by CA. To address these gaps, physiological, histochemical, and biochemical approaches were applied to investigate CA-facilitated cadmium (Cd) tolerance in the roots of tobacco (Nicotiana tabacum) seedlings. Treatment with CdCl2 at 20 µM for 72 h resulted in the significant decrease in root elongation by 40.39% as compared to control. CA alleviated Cd-inhibited root elongation in dose- and time-dependent manners. The addition of CA at 20 µM induced significant increase in root elongation by 42.58% as compared to Cd treatment alone. CA abolished Cd-induced ROS (reactive oxygen species) accumulation, lipid peroxidation, loss of membrane integrity, cell death, and free Cd2+ accumulation in roots. CA blocked the Cd-induced increase in the endogenous H2S level through the down-regulation of d-cysteine desulfhydrase (DCD) expression. H2S scavenger hypotaurine (HT) or potent H2S-biosynthetic inhibitor dl-propargylglicine (PAG) were able mimic the action of CA on the blockade of Cd-induced H2S accumulation, cell death, and growth inhibition. Enhancement of the endogenous H2S level with NaHS (H2S donor) abrogated all the beneficial capabilities of CA, HT, and PAG. Collectively, these results suggest that CA has great potential to confer plant tolerance against Cd stress, which is closely associated with its capability to inhibit Cd-induced H2S production. This study not only provides evidences for the regulation of plant physiology by CA but also sheds new light on the cross-talk between CA and H2S in physiological modulations.

Cinnamaldehyde promotes root branching by regulating endogenous hydrogen sulfide.

BACKGROUND: Cinnamaldehyde (CA) has been widely applied in medicine and food preservation. However, whether and how CA regulates plant physiology is largely unknown. To address these gaps, the present study investigated the beneficial effect of CA on root branching and its possible biochemical mechanism. RESULTS: The lateral root (LR) formation of pepper seedlings could be markedly induced by CA at specific concentrations without any inhibitory effect on primary root (PR) growth. CA could induce the generation of endogenous hydrogen sulfide (H2S) by increasing the activity of L-cysteine desulfhydrase in roots. By fluorescently tracking endogenous H2S in situ, it could be clearly observed that H2S accumulated in the outer layer cells of the PR where LRs emerge. Sodium hydrosulfide (H2S donor) treatment induced LR formation, while hypotaurine (H2S scavenger) showed an adverse effect. The addition of hypotaurine mitigated the CA-induced increase in endogenous H2S level, which in turn counteracted the inducible effect of CA on LR formation. CONCLUSION: CA showed great potential in promoting LR formation, which was mediated by endogenous H2S. These results not only shed new light on the application of CA in agriculture but also extend the knowledge of H2S signaling in the regulation of root branching.

[Effect of Schistosoma japonicum infection on serum lipid status in mice].

OBJECTIVE: To investigate the effect of Schistosoma japonicum infection on lipid status in mouse serum. METHODS: Twenty-four ICR mice were randomly divided into two groups, fed a high fat diet (HFD) or a normal diet (ND). On the 28th day, 6 mice from each group were infected with double sex cercariae of S. japonicum via abdominal skin (150 cercariae/mouse). At 42 days post-infection, the mice were sacrificed and the sera were collected. Other 36 ICR mice were randomly divided into three groups fed on normal diet. Mice in the first group were infected with S. japonicum single-sex cercariae via abdominal skin (150 cercariae/mouse) and sacrificed on Day 42. Mice in the second group were intraperitoneally injected with 10,000 S. japonicum eggs and serum samples were collected at Day 4 and Day 7. Mice in the third group were intraperitoneally injected with soluble egg antigen (SEA) every day for 6 days [1 mg/(mice x d)] and serum was collected at Day 7. Mice from control group were fed a high fat diet or a normal diet without infection. Serum levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL), and low density lipoprotein (LDL) were measured. RESULTS: Compared with the uninfected controls, the serum levels of TC, TG, HDL, and LDL decreased significantly in double-sex cercariae infected-mice fed on a high fat diet or a normal diet (P < 0.05). In HFD group, serum TC[(1.45 +/- 0.31) mmol/L], TG [(0.17 +/- 0.06)mmol/L], HDL [(1.11 +/- 0.26) mmol/L] and LDL [(0.44 +/- 0.15)mmol/L] levels in mice infected with double-sex cercariae were lower than that of uninfected mice [(7.86 +/- 0.07)mmol/L, (0.23 +/- 0.07) mmol/L, (4.96 +/- 0.81) mmol/L, (3.93 +/- 0.29) mmol/L] (P < 0.05) . In ND group, serum TC [(1.03 +/- 0.08) mmol/L] , TG [(0.17 +/- 0.03) mmol/L], HDL [(0.84 +/- 0.02) mmol/L], and LDL [(0.09 +/- 0.02) mmol/L] levels in mice infected with double-sex cercariae were lower than that of uninfected mice [(1.85 +/- 0.05) mmol/L, (0.90 +/- 0.14) mmol/L (1.38 +/- 0.18) mmol/L, (0.15 +/- 0.01) mmol/L, respectively] (P < 0.05) . The mice serum lipid indices had no obvious change after single-sex cercariae or egg injection (P > 0.05). Serum TC [(1.07 +/- 0.15) mmol/L], TG [(1.06 +/- 0.15) mmol/L], HDL [(0.71 +/- 0.14) mmol/L], and LDL [(0.05 +/- 0.04) mmol/L] levels in SEA injected mice were lower than that of the control group [(1.81 +/- 0.06) mmol/L, (2.15 +/- 0.13) mmol/L, (1.160.15) mmol/L, (0.16 +/- 0.03) mmol/L] (P < 0.05). CONCLUSION: Schistosoma japonicum infection can decrease serum lipid concentrations in the mouse host.

G0 arrest gene patterns to predict the prognosis and drug sensitivity of patients with lung adenocarcinoma.

G0 arrest (G0A) is widely recognized as a crucial factor contributing to tumor relapse. The role of genes related to G0A in lung adenocarcinoma (LUAD) was unclear. This study aimed to develop a gene signature based on for LUAD patients and investigate its relationship with prognosis, tumor immune microenvironment, and therapeutic response in LUAD. We use the TCGA-LUAD database as the discovery cohort, focusing specifically on genes associated with the G0A pathway. We used various statistical methods, including Cox and lasso regression, to develop the model. We validated the model using bulk transcriptome and single-cell transcriptome datasets (GSE50081, GSE72094, GSE127465, GSE131907 and EMTAB6149). We used GSEA enrichment and the CIBERSORT algorithm to gain insight into the annotation of the signaling pathway and the characterization of the tumor microenvironment. We evaluated the response to immunotherapy, chemotherapy, and targeted therapy in these patients. The expression of six genes was validated in cell lines by quantitative real-time PCR (qRT-PCR). Our study successfully established a six-gene signature (CHCHD4, DUT, LARP1, PTTG1IP, RBM14, and WBP11) that demonstrated significant predictive power for overall survival in patients with LUAD. It demonstrated independent prognostic value in LUAD. To enhance clinical applicability, we developed a nomogram based on this gene signature, which showed high reliability in predicting patient outcomes. Furthermore, we observed a significant association between G0A-related risk and tumor microenvironment as well as drug susceptibility, highlighting the potential of the gene signature to guide personalized treatment strategies. The expression of six genes were significantly upregulated in the LUAD cell lines. This signature holds the potential to contribute to improved prognostic prediction and new personalized therapies specifically for LUAD patients.

Nutrigenetic and Epigenetic Mechanisms of Maternal Nutrition-Induced Glucolipid Metabolism Changes in the Offspring.

Maternal nutrition during pregnancy regulates the offspring's metabolic homeostasis, including insulin sensitivity and the metabolism of glucose and lipids. The fetus undergoes a crucial period of plasticity in the uterus; metabolic changes in the fetus during pregnancy caused by maternal nutrition not only influence fetal growth and development but also have a long-term or even life-long impact for the offspring. Epigenetic modifications, such as DNA methylation, histone modification, and non-coding RNAs, play important roles in intergenerational and transgenerational effects. In this context, this narrative review comprehensively summarizes and analyzes the molecular mechanisms underlying how maternal nutrition, including a high-fat diet, polyunsaturated fatty acid diet, methyl donor nutrient supplementation, feed restriction, and protein restriction during pregnancy, impacts the genes involved in glucolipid metabolism in the liver, adipose tissue, hypothalamus, muscle, and oocytes of the offspring in terms of the epigenetic modifications. This will provide a foundation for the further exploration of nutrigenetic and epigenetic mechanisms for integrative mother-child nutrition and promotion of the offspring's health through the regulation of maternal nutrition during pregnancy. Note: This paper is part of the Nutrition Reviews Special Collection on Precision Nutrition.

Yaks Are Dependent on Gut Microbiota for Survival in the Environment of the Qinghai Tibet Plateau.

The yak (Poephagus grunniens) has evolved unique adaptations to survive the harsh environment of the Qinghai-Tibetan Plateau, while their gut microorganisms play a crucial role in maintaining the health of the animal. Gut microbes spread through the animal population not only by horizontal transmission but also vertically, which enhances microbial stability and inheritance between generations of the population. Homogenization of gut microbes in different animal species occurs in the same habitat, promoting interspecies coexistence. Using the yak as a model animal, this paper discusses the adaptive strategies under extreme environments, and how the gut microbes of the yak circulate throughout the Tibetan Plateau system, which not only affects other plateau animals such as plateau pikas, but can also have a profound impact on the health of people. By examining the relationships between yaks and their gut microbiota, this review offers new insights into the adaptation of yaks and their ecological niche on the Qinghai-Tibetan plateau.

Effect of Different Slow-Release Urea on the Production Performance, Rumen Fermentation, and Blood Parameter of Angus Heifer.

This study investigated the effect of replacing part of the dietary soybean meal with either polymer-coated urea or gelatinized starch urea on the production performance, blood indexes, and ruminal fermentation of Angus heifers. A total of 210 purebred Angus cattle (BW = 314.26 kg) were divided into three groups: the no urea group (CON), the polymer-coated urea group (PCU), and the gelatinized starch urea group (GSU); 20 g/kg polymer-coated urea or 25 g/kg gelatinized starch urea was used to replace part of soybean meal in the concentrate feed, according to the principle of isometabolic energy and isonitrogenous. The result showed that the PCU group had higher ADG and ADF apparent digestibility, while it had a lower feed-weight ratio. On the 86th day, the serum albumin (ALB) content in the PCU group was significantly higher than that in the CON group. In rumen, compared with the CON group, the contents of acetic acid and total volatile fatty acid were significantly higher in the PCU group, whereas butyric acid and propionic acid were significantly higher in the PCU group and GSU group. Ruminal bacterial diversity analysis found that the abundance of Firmicutes was higher in the PCU group at the phylum level, and an inverse result was observed in Bacteroidetes. The abundance of Paraprevotella was higher in the PCU group, whereas higher abundance of Prevotella was found in the GSU group at the genus level. These results indicate that slow-release urea can replace part of soybean meal in the diet, and the amount of substitution in this trial had no diverse effect on the performance of Angus heifers.

Copper oxide nanoparticles impairs oocyte meiosis maturation by inducing mitochondrial dysfunction and oxidative stress.

Copper oxides nanoparticles (CuO NPs) are widely used for a variety of industrial and life science applications. In addition to cause neurotoxicity, hepatotoxicity, immunotoxicity, CuO NPs have also been reported to adversely affect the reproductive system in animals; However, little is known about the effects and potential mechanism of CuO NPs exposure on oocyte quality, especially oocyte maturation. In the present study, we reported that CuO NPs exposure impairs the oocyte maturation by disrupting meiotic spindle assembly and chromosome alignment, as well as kinetochore-microtubule attachment. In addition, CuO NPs exposure also affects the acetylation level of α-tubulin in mice oocyte, which hence impairs microtubule dynamics and organization. Besides, CuO NPs exposure would result in the mis-localization of Juno and Ovastacin, which might be one of the critical factors leading to the failure of oocyte maturation. Finally, CuO NPs exposure impairs the mitochondrial distribution and induced high levels of ROS, which led to the accumulation of DNA damage and occurrence of apoptosis. In summary, our results indicated that CuO NPs exposure had potential toxic effects on female fertility and led to the poor oocyte quality in female mice.

Undernutrition Disrupts Cecal Microbiota and Epithelium Interactions, Epithelial Metabolism, and Immune Responses in a Pregnant Sheep Model.

Undernutrition may change cecal microbiota-epithelium interactions to influence cecal feed fermentation, nutrient absorption and metabolism, and immune function. Sixteen late-gestation Hu-sheep were randomly divided into control (normal feeding) and treatment (feed restriction) groups to establish an undernourished sheep model. Cecal digesta and epithelium were collected to analyze microbiota-host interactions based on 16S rRNA gene and transcriptome sequencing. Results showed that cecal weight and pH were decreased, volatile fatty acids and microbial proteins concentrations were increased, and epithelial morphology was changed upon undernutrition. Undernutrition reduced the diversity, richness, and evenness of cecal microbiota. The relative abundances of cecal genera involved in acetate production (Rikenellaceae dgA-11 gut group, Rikenellaceae RC9 gut group, and Ruminococcus) and negatively correlated with butyrate proportion (Clostridia vadinBB60 group_norank) were decreased, while genera related to butyrate (Oscillospiraceae_uncultured and Peptococcaceae_uncultured) and valerate (Peptococcaceae_uncultured) production were increased in undernourished ewes. These findings were consistent with the decreased molar proportion of acetate and the increased molar proportions of butyrate and valerate. Undernutrition changed the overall transcriptional profile and substance transport and metabolism in cecal epithelium. Undernutrition suppressed extracellular matrix-receptor interaction and intracellular phosphatidyl inositol 3-kinase (PI3K) signaling pathway then disrupted biological processes in cecal epithelium. Moreover, undernutrition repressed phagosome antigen processing and presentation, cytokine-cytokine receptor interaction, and intestinal immune network. In conclusion, undernutrition affected cecal microbial diversity and composition and fermentation parameters, inhibited extracellular matrix-receptor interaction and the PI3K signaling pathway, and then disrupted epithelial proliferation and renewal and intestinal immune functions. Our findings exposed cecal microbiota-host interactions upon undernutrition and contribute to their further exploration. IMPORTANCE Undernutrition is commonly encountered in ruminant production, especially during pregnancy and lactation in females. Undernutrition not only induces metabolic diseases and threatens pregnant mothers' health, but also inhibits fetal growth and development, leading to weakness or even death of fetuses. Cecum works importantly in hindgut fermentation, providing volatile fatty acids and microbial proteins to the organism. Intestinal epithelial tissue plays a role in nutrient absorption and transport, barrier function, and immune function. However, little is known about cecal microbiota and epithelium interactions upon undernutrition. Our findings showed that undernutrition affected bacterial structures and functions, which changed fermentation parameters and energy regimens, and therefore affected the substance transport and metabolism in cecal epithelium. Extracellular matrix-receptor interactions were inhibited, which repressed cecal epithelial morphology and cecal weight via the PI3K signaling pathway and lowered immune response function upon undernutrition. These findings will help in further exploring microbe-host interactions.