Toxicological effects induced by two carbamates on earthworms (Eisenia fetida): Acute toxicity, arrested regeneration and underlying mechanisms.

Eisenia fetida is recognised as advantageous model species in ecotoxicological and regeneration investigations. The intensive utilization of carbamate pesticides (CARs) imposes heavy residue burdens and grave hazards on edaphic environments as well as soil fauna therein. However, precise mechanisms whereby the specific CAR exerted toxic effects on earthworms remain largely elusive, notably from regenerative perspective. Herein, acute responses and regenerative toxicity of two carbamates (metolcarb, MEB and fenoxycarb, FEB) against E. fetida were dissected using biochemical, histological as well as molecular approaches following OECD guidelines at the cellular, tissue and organismal level. The acute toxicity data implied that MEB/FEB were very toxic/medium to extremely toxic, respectively in filter paper contact test and low to medium toxic/low toxic, respectively in artificial soil test. Chronic exposure to MEB and FEB at sublethal concentrations significantly mitigated the soluble protein content, protein abundance while enhanced the protein carbonylation level. Moreover, severely retarded posterior renewal of amputated earthworms was noticed in MEB and FEB treatments relative to the control group, with pronouncedly compromised morphology, dwindling segments and elevated cell apoptosis of blastema tissues, which were mediated by the rising Sox2 and decreasing TCTP levels. Taken together, these findings not only presented baseline toxicity cues for MEB and FEB exposure against earthworms, but also yielded mechanistic insights into regenerative toxicity upon CAR exposure, further contributing to the environmental risk assessment and benchmark formulation of agrochemical pollution in terrestrial ecosystem.

Development of Specific Monoclonal Antibodies against Porcine RIG-I-like Receptors Revealed the Species Specificity.

The RIG-I-like receptors (RLRs) play critical roles in sensing and combating viral infections, particularly RNA virus infections. However, there is a dearth of research on livestock RLRs due to a lack of specific antibodies. In this study, we purified porcine RLR proteins and developed monoclonal antibodies (mAbs) against porcine RLR members RIG-I, MDA5 and LGP2, for which one, one and two hybridomas were obtained, respectively. The porcine RIG-I and MDA5 mAbs each targeted the regions beyond the N-terminal CARDs domains, whereas the two LGP2 mAbs were both directed to the N-terminal helicase ATP binding domain in the Western blotting. In addition, all of the porcine RLR mAbs recognized the corresponding cytoplasmic RLR proteins in the immunofluorescence and immunochemistry assays. Importantly, both RIG-I and MDA5 mAbs are porcine specific, without demonstrating any cross-reactions with the human counterparts. As for the two LGP2 mAbs, one is porcine specific, whereas another one reacts with both porcine and human LGP2. Thus, our study not only provides useful tools for porcine RLR antiviral signaling research, but also reveals the porcine species specificity, giving significant insights into porcine innate immunity and immune biology.

Lifestyle intervention in obese pregnancy and cardiac remodelling in 3-year olds: children of the UPBEAT RCT.

BACKGROUND/OBJECTIVES: Obesity in pregnancy has been associated with increased childhood cardiometabolic risk and reduced life expectancy. The UK UPBEAT multicentre randomised control trial was a lifestyle intervention of diet and physical activity in pregnant women with obesity. We hypothesised that the 3-year-old children of women with obesity would have heightened cardiovascular risk compared to children of normal BMI women, and that the UPBEAT intervention would mitigate this risk. SUBJECTS/METHODS: Children were recruited from one UPBEAT trial centre. Cardiovascular measures included blood pressure, echocardiographic assessment of cardiac function and dimensions, carotid intima-media thickness and heart rate variability (HRV) by electrocardiogram. RESULTS: Compared to offspring of normal BMI women (n = 51), children of women with obesity from the trial standard care arm (n = 39) had evidence of cardiac remodelling including increased interventricular septum (IVS; mean difference 0.04 cm; 95% CI: 0.018 to 0.067), posterior wall (PW; 0.03 cm; 0.006 to 0.062) and relative wall thicknesses (RWT; 0.03 cm; 0.01 to 0.05) following adjustment. Randomisation of women with obesity to the intervention arm (n = 31) prevented this cardiac remodelling (intervention effect; mean difference IVS -0.03 cm (-0.05 to -0.008); PW -0.03 cm (-0.05 to -0.01); RWT -0.02 cm (-0.04 to -0.005)). Children of women with obesity (standard care arm) compared to women of normal BMI also had elevated minimum heart rate (7 bpm; 1.41 to 13.34) evidence of early diastolic dysfunction (e prime) and increased sympathetic nerve activity index by HRV analysis. CONCLUSIONS: Maternal obesity was associated with left ventricular concentric remodelling in 3-year-old offspring. Absence of remodelling following the maternal intervention infers in utero origins of cardiac remodelling. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: The UPBEAT trial is registered with Current Controlled Trials, ISRCTN89971375.

Lactoferrin Attenuates Intestinal Barrier Dysfunction and Inflammation by Modulating the MAPK Pathway and Gut Microbes in Mice.

BACKGROUND: Deoxynivalenol (DON) is a major mycotoxin present in staple foods (particularly in cereal products) that induces intestinal inflammation and disrupts intestinal integrity. Lactoferrin (LF) is a multifunctional protein that contributes to maintaining intestinal homeostasis and improving host health. However, the protective effects of LF on DON-induced intestinal dysfunction remain unclear. OBJECTIVES: This study aimed to investigate the effects of LF on DON-induced intestinal dysfunction in mice, and its underlying protective mechanism. METHODS: Male BALB/c mice (5 wk old) with similar body weights were divided into 4 groups (n = 6/group) and treated as follows for 5 wk: Veh [peroral vehicle daily, commercial (C) diet]; LF (peroral 10 mg LF/d, C diet); DON (Veh, C diet containing 12 mg DON/kg); and LF + DON (peroral 10 mg LF/d, DON diet). Intestinal morphology, tight junction proteins, cytokines, and microbial community were determined. Data were analyzed by 2-factor ANOVA or Kruskal-Wallis test. RESULTS: The DON group exhibited lower final body weight (-12%), jejunal villus height (VH; -41%), and jejunal occludin expression (-36%), and higher plasma IL-1ß concentration (+85%) and jejunal Il1b mRNA expression (+98%) compared with the Veh group (P < 0.05). In contrast, final body weight (+19%), jejunal VH (+49%), jejunal occludin (+53%), and intelectin 1 protein expression (+159%) were greater in LF + DON compared with DON (P < 0.05). Additionally, jejunal Il1b mRNA expression (-31%) and phosphorylation of p38 and extracellular signal regulated kinase 1/2 (-40% and - 38%) were lower in LF + DON compared with DON (P < 0.05). Furthermore, the relative abundance of Clostridium XIVa (+181%) and colonic butyrate concentration (+53%) were greater in LF + DON compared with DON (P < 0.05). CONCLUSIONS: Our study highlights a promising antimycotoxin approach using LF to alleviate DON-induced intestinal dysfunction by modulating the mitogen-activated protein kinase pathway and gut microbial community in mice.

Targeted inhibition of PPARα ameliorates CLA-induced hypercholesterolemia via hepatic cholesterol biosynthesis reprogramming.

BACKGROUND & AIMS: Disruption of lipid metabolism is largely linked to metabolic disorders, such as hypercholesterolemia (HCL) and liver steatosis. While cholesterol metabolic re-programmers can serve as targets for relevant interventions. Here we explored the dietary conjugated linoleic acids (CLA)-induced HCL in mice and the molecular regulation behind it. METHODS: A high dose of CLA supplementation in the diet was used to induce HCL in mice and was found to cause a hyper-activated cholesterol biosynthesis programme in the liver, leading to cholesterol metabolism dysregulation. The effects of a small-molecule drug targeting PPARα, i.e., GW6471 were studied in vivo in mice fed diets with CLA supplementation for 28 days, and in primary hepatocytes derived from HCL-mice in vitro. RESULTS: We demonstrate that CLA induced HCL and liver steatosis through multiple pathways. Among which was the PPARα-mediated cholesterogenesis. It was found to cooperate with SREBP2 via binding to Hmgcr and Dhcr7 (genes encoding key enzymes of the cholesterol biosynthetic pathway) and recruits the histone marks H3K27ac and H3K4me1 and cofactors. PPARα inhibition disrupts its physical association with SREBP2 by blocking cobinding of PPARα and SREBP2 to the genomic DNA response element. We showed that NR RORγ functions as an essential mediator that facilitates the interaction of PPARα and SREBP2 to modulate the cholesterol biosynthesis genes expression. CONCLUSIONS: Our study unravels that the small-molecule compound GW6471 exerts an attractive therapeutic effect for CLA-induced HCL, involving multiple pathways with the "PPARα-RORγ-SREBP2" being a potential complex player in this hepatic cholesterol biosynthesis programming.

Direct cardiac versus systemic effects of inorganic nitrite on human left ventricular function.

Inorganic nitrite is a source of nitric oxide (NO) and is considered as a potential therapy in settings where endogenous NO bioactivity is reduced and left ventricular (LV) function impaired. However, the effects of nitrite on human cardiac contractile function, and the extent to which these are direct or indirect, are unclear. We studied 40 patients undergoing diagnostic cardiac catheterization who had normal LV systolic function and were not found to have obstructive coronary disease. They received either an intracoronary sodium nitrite infusion (8.7-26 µmol/min, n = 20) or an intravenous sodium nitrite infusion (50 µg/kg/min, n = 20). LV pressure-volume relations were recorded. The primary end point was LV end-diastolic pressure (LVEDP). Secondary end points included indices of LV systolic and diastolic function. Intracoronary nitrite infusion induced a significant reduction in LVEDP, LV end-diastolic pressure-volume relationship (EDPVR), and the time to LV end-systole (LVEST) but had no significant effect on LV systolic function or systemic hemodynamics. Intravenous nitrite infusion induced greater effects, with significant decreases in LVEDP, EDPVR, LVEST, LV dP/dtmin, tau, and mean arterial pressure. Inorganic nitrite has modest direct effects on human LV diastolic function, independent of LV loading conditions and without affecting LV systolic properties. However, the systemic administration of nitrite has larger effects on LV diastolic function, which are related to reduction in both preload and afterload. These contractile effects of inorganic nitrite may indicate a favorable profile for conditions characterized by LV diastolic dysfunction.NEW & NOTEWORTHY This is the first study to assess the direct and indirect effects of inorganic nitrite on invasive measures of left ventricular function in humans in vivo. Inorganic nitrite has a modest direct myocardial effect, improving diastolic function. Systemic administration of nitrite has larger effects related to alterations in cardiac preload and afterload. The changes induced by nitrite appear favorable for potential use in conditions characterized by LV diastolic dysfunction.

First-phase ejection fraction by cardiovascular magnetic resonance predicts outcomes in aortic stenosis.

BACKGROUND: First-phase ejection fraction (EF1; the ejection fraction measured during active systole up to the time of maximal aortic flow) measured by transthoracic echocardiography (TTE) is a powerful predictor of outcomes in patients with aortic stenosis. We aimed to assess whether cardiovascular magnetic resonance (CMR) might provide more precise measurements of EF1 than TTE and to examine the correlation of CMR EF1 with measures of fibrosis. METHODS: In 141 patients with at least mild aortic stenosis, we measured CMR EF1 from a short-axis 3D stack and compared its variability with TTE EF1, and its associations with myocardial fibrosis and clinical outcome (aortic valve replacement (AVR) or death). RESULTS: Intra- and inter-observer variation of CMR EF1 (standard deviations of differences within and between observers of 2.3% and 2.5% units respectively) was approximately 50% that of TTE EF1. CMR EF1 was strongly predictive of AVR or death. On multivariable Cox proportional hazards analysis, the hazard ratio for CMR EF1 was 0.93 (95% confidence interval 0.89-0.97, p = 0.001) per % change in EF1 and, apart from aortic valve gradient, CMR EF1 was the only imaging or biochemical measure independently predictive of outcome. Indexed extracellular volume was associated with AVR or death, but not after adjusting for EF1. CONCLUSIONS: EF1 is a simple robust marker of early left ventricular impairment that can be precisely measured by CMR and predicts outcome in aortic stenosis. Its measurement by CMR is more reproducible than that by TTE and may facilitate left ventricular structure-function analysis.

First phase ejection fraction in aortic stenosis: A useful new measure of early left ventricular systolic dysfunction.

In aortic stenosis (AS), a left ventricular (LV) ejection fraction (EF) <50% or symptoms are class I indications for aortic valve intervention. However, an EF <50% may be too conservative since subendocardial fibrosis may already have developed. An earlier marker of LV systolic dysfunction is therefore needed and first phase EF (EF1) is a promising new candidate. It is the EF measured over early systole to the point of maximum transaortic blood flow. It may be low in the presence of preserved total LV EF since the heart may compensate by recruiting myosin motors in later systole. The EF1 is inversely related to the grade of AS and directly related to markers of subendocardial fibrosis like late gadolinium enhancement on cardiac magnetic resonance scanning. A reduced EF1 (<25%) predicts adverse clinical events better that total EF and global longitudinal strain. We suggest that it is worth exploring as an indication for surgery in patients with asymptomatic severe AS.

The Circadian Physiology: Implications in Livestock Health.

Circadian rhythms exist in almost all types of cells in mammals. Thousands of genes exhibit approximately 24 h oscillations in their expression levels, making the circadian clock a crucial regulator of their normal functioning. In this regard, environmental factors to which internal physiological processes are synchronized (e.g., nutrition, feeding/eating patterns, timing and light exposure), become critical to optimize animal physiology, both by managing energy use and by realigning the incompatible processes. Once the circadian clock is disrupted, animals will face the increased risks of diseases, especially metabolic phenotypes. However, little is known about the molecular components of these clocks in domestic species and by which they respond to external stimuli. Here we review evidence for rhythmic control of livestock production and summarize the associated physiological functions, and the molecular mechanisms of the circadian regulation in pig, sheep and cattle. Identification of environmental and physiological inputs that affect circadian gene expressions will help development of novel targets and the corresponding approaches to optimize production efficiency in farm animals.

Hepatic leukocyte immunoglobulin-like receptor B4 (LILRB4) attenuates nonalcoholic fatty liver disease via SHP1-TRAF6 pathway.

Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent liver pathology characterized by hepatic steatosis and commonly accompanied by systematic inflammation and metabolic disorder. Despite an accumulating number of studies, no pharmacological strategy is available to treat this condition in the clinic. In this study, we applied extensive gain- and loss-of-function approaches to identify the key immune factor leukocyte immunoglobulin-like receptor B4 (LILRB4) as a negative regulator of NAFLD. The hepatocyte-specific knockout of LILRB4 (LILRB4-HKO) exacerbated high-fat diet-induced insulin resistance, glucose metabolic imbalance, hepatic lipid accumulation, and systematic inflammation in mice, whereas LILRB4 overexpression in hepatocytes showed a completely opposite phenotype relative to that of LILRB4-HKO mice when compared with their corresponding controls. Further investigations of molecular mechanisms demonstrated that LILRB4 recruits SHP1 to inhibit TRAF6 ubiquitination and subsequent inactivation of nuclear factor kappa B and mitogen-activated protein kinase cascades. From a therapeutic perspective, the overexpression of LILRB4 in a genetic model of NAFLD, ob/ob mice, largely reversed the inherent hepatic steatosis, inflammation, and metabolic disorder. CONCLUSION: Targeting hepatic LILRB4 to improve its expression or activation represents a promising strategy for the treatment of NAFLD as well as related liver and metabolic diseases. (Hepatology 2018;67:1303-1319).

Cardiac effects of 6 months' dietary nitrate and spironolactone in patients with hypertension and with/at risk of type 2 diabetes, in the factorial design, double-blind, randomized controlled VaSera trial.

AIMS: The aims of the present study were to explore whether a long-term intervention with dietary nitrate [(NO3- ), a potential tolerance-free source of beneficial vasoactive nitric oxide] and spironolactone (to oppose aldosterone's potential deleterious cardiovascular effects) improve cardiac structure/function, independently of blood pressure (BP), in patients with/at risk of type 2 diabetes (a population at risk of heart failure). METHODS: A subsample of participants in our double-blind, randomized, factorial-design intervention (VaSera) trial of active beetroot juice as a nitrate source (≤11.2 mmol) or placebo (nitrate depleted) beetroot juice, and either ≤50 mg spironolactone or ≤16 mg doxazosin (control), had transthoracic cardiac ultrasounds at baseline (n = 105), and at 3 months and 6 months (n = 87) after the start of the intervention. Analysis was by modified intent-to-treat. RESULTS: Nitrate-containing juice (n = 40) decreased left ventricular (LV) end-diastolic volume {-6.3 [95% confidence interval (CI) -11.1, -1.6] ml} and end-systolic volume [-3.2 (95% CI -5.9, -0.5) ml], and increased end-diastolic mass/volume ratio [+0.04 (95% CI 0.00, 0.07)], relative to placebo juice (n = 47). Spironolactone (n = 44) reduced relative wall thickness compared with doxazosin (n = 43) [-0.01 (95% CI -0.02, -0.00)]. Although spironolactone reduced LV mass index relative to baseline [-1.48 (95% CI -2.08, -0.88) g m-2.7 ], there was no difference vs. doxazosin [-0.85 (95% CI -1.76, 0.05) g m-2.7 ]. Spironolactone also decreased the E/A ratio [-0.12 (95% CI -0.19, -0.04)] and increased S' (a tissue-Doppler systolic function index) by 0.52 (95% CI 0.05, 1.0) cm s-1 . BP did not differ between the juices, or between the drugs. CONCLUSIONS: Six months' dietary nitrate decreased LV volumes ~5%, representing new, sustained, BP-independent benefits on cardiac structure, extending mechanisms characterized in preclinical models of heart failure. Spironolactone's effects on cardiac remodelling and systolic-diastolic function, although confirmatory, were independent of BP.

Central blood pressure and measures of early vascular disease in children with ADPKD.

BACKGROUND: There is growing recognition of hypertension in a significant proportion of children with ADPKD. In this study, we assessed blood pressure and cardiovascular status in children with ADPKD. METHODS: A prospective two-centre observational study of children (< 18 years) with ADPKD was compared against age- and BMI-matched healthy controls. Children underwent peripheral BP (pBP) measured using an aneroid sphygmomanometer and auscultation, 24-h ambulatory BP monitoring (ABPM), non-invasive central BP (cBP) measurement, carotid-femoral pulse wave velocity (PWVcf) measured using applanation tonometry and measurement of indexed left ventricular mass (LVMI) using echocardiography. This study received independent ethical approval. RESULTS: Forty-seven children with ADPKD and 49 healthy controls were recruited (median age 11 years vs. 12 years). Children with ADPKD had significantly higher systolic pBP (mean 112 ± 13.5 mmHg vs. 104 ± 11 mmHg, p < 0.001), higher systolic cBP (mean 97 ± 12.8 mmHg vs. 87 ± 9.8 mmHg, p < 0.001) and lower pulse pressure amplification ratio (1.59 ± 0.2 vs. 1.67 ± 0.1, p = 0.04) compared to healthy children. Thirty-five percent of children with ADPKD showed a lack of appropriate nocturnal dipping on 24-h ABPM. There was no difference in PWVcf between children with ADPKD and healthy children (mean 5.74 ± 1 m/s vs. 5.57 ± 0.9 m/s, p = 0.46). Those with ADPKD had a significantly higher LVMI (mean 30.4 ± 6.6 g/m2.7 vs. 26.2 ± 6.2 g/m2.7, p = 0.01). CONCLUSIONS: These data highlight the high prevalence of hypertension in children with ADPKD, also demonstrating early cardiovascular dysfunction with increased LVMI and reduced PP amplification despite preserved PWVcf, when compared with healthy peers. These early cardiovascular abnormalities are likely to be amenable to antihypertensive therapy, reinforcing the need for routine screening of children with ADPKD.

Silencing of triazophos-induced Hexokinase-1-like reduces fecundity in Nilaparvata lugens (Stål) (Hemiptera: Delphacidae).

Hexokinase is a rate-limiting enzyme that plays pivotal roles in glucose homeostasis and energy metabolism via glucose (Glc) phosphorylation and Glc signaling mediation. Previous investigations have revealed the modulatory role of Hexokinase (Hex) genes involved in proper glucose regulation during insect diapause and embryo development, whereas whether it functions in insect fecundity remains largely unknown. We aimed to explore the relationship between Triazophos (TZP)-induced Hex-1 and fecundity of female Nilaparvata lugens. In this study, Hex-1 expression were characterized at different developmental stages and in various tissues of N. lugens, with the highest expression registered in brain tissues and 5th instar nymph. The present findings indicated that TZP + dsHex-1 silencing significantly reduced protein synthesis, including the fat body and ovarian protein content of female adults. Meanwhile, the glycometabolism with respect to the soluble sugar, trehalose and glucose content in female adults were strikingly influenced as a result of Hex-1 knockdown. The relative transcript level of Hex-1, vitellogenin (NlVg) and vitellogenin receptor (NlVgR) considerably decreased in TZP + dsHex-1 treated females compared to TZP and TZP + dsGFP-treated groups. More importantly, TZP + dsHex-1 silencing led to reduced number of eggs laid and vitellogenin (Vg) accumulation as well as retarded ovary development compared with TZP-treated and TZP + dsGFP-treated groups. Taken together, it is proposed that Hex-1 implicates in N. lugens fecundity by exerting profound effects on glycometabolism, protein sythesis and NlVg expression.

Silencing pyruvate kinase (NlPYK) leads to reduced fecundity in brown planthoppers, Nilaparvata lugens (Stål) (Hemiptera: Delphacidae).

Pyruvate kinase (PYK) operates in the glycolytic pathway, responsible for regulating the balance between glycolysis and gluconeogenesis. The previous work indicates PYK acts in development of Drosophila embryos and in embryonic muscle growth, from which it may be inferred that PYK acts in insect fecundity. More to the point, as a central enzyme in the glycolytic pathway, PYK acts in many energy-spending functions in most organisms. On the background findings that triazophos (TZP) stimulates fecundity via increase activities of several genes in brown planthoppers, Nilaparvata lugens, we investigated the combined influence of TZP and silencing a N. lugens PYK (NlPYK) on reproduction-linked biological performance parameters. Here, we report that TZP+dsNlPYK treatments led to reduced (by 26%) ovarian, but not fat body, protein content relative to controls. Ovarian (35%) and fat body (54%) soluble sugar contents were reduced. TZP+dsNlPYK treatments also led to reduced (by about 24%) fecundity, expressed as numbers of eggs laid. These data show directly that NlPYK acts in insect fecundity, probably via increases in glucose metabolism.

Dissipation kinetics, safety evaluation, and preharvest interval assessment of trichlorfon application on rice.

Nowadays, there is an urgent need for the investigation of the field dissipation and assessment of the preharvest interval for trichlorfon residues on rice. To protect consumers from potential health risks, this study can provide references for the safe application of trichlorfon in the rice fields. Results of the field dissipation study showed that the dissipation dynamic equations of trichlorfon were based on the first-order reaction dynamic equations and that the dissipation rates vary among rice plant, brown rice, rice bran, soil, and water. The 2-year field trials conducted in Yangzhou and Xiaogan suggested the interval of each application for trichlorfon on rice to be at least 7 days when 80 % trichlorfon SP was sprayed with a dose ranges between 80 and 160 a.i g/667 m(2). Additionally, the preharvest interval of the last application should be at least 15 days to ensure the amounts of residues below the maximum residue limits of trichlorfon on brown rice (0.1 mg/kg).

Echocardiography predicts major adverse cardiovascular events after renal transplantation.

INTRODUCTION: Cardiovascular disease is a leading cause of morbidity and mortality after renal transplantation. We analysed whether pre-transplant transthoracic echocardiograms (TTE) predicted major adverse cardiovascular events (MACE) after transplant. METHODS: We retrospectively analysed clinical and TTE data from patients having renal transplantation at a single centre between 1 January 2000 and 31 December 2010. The TTE were classified as: group A - normal; group B - mild abnormalities expected in renal failure; group C - moderate to severe abnormalities likely to change management. They were also scored based on four independent risk factors [age ≥50, left ventricular (LV) end systolic diameter ≥3.5 cm, LV wall thickness ≥1.4 cm and mitral annulus calcification]. Post-transplantation clinical notes were examined for MACE (death, stroke, myocardial infarction, and surgical or percutaneous revascularisation). RESULTS: There were 343 patients, mean age 47 (range 21-83) years, 210 of whom were male. MACE occurred in 29 (8.5%) at a mean of 3.6 (SD 3.3) years after transplantation. They were older (p ≤ 0.001), had larger LV mass (p = 0.02), LV wall thickness (p = 0.008) and left atrial size (p = 0.001) than those without MACE. The MACE rate for groups A, B and C were 1.8, 13.6 and 16.4% (p ≤ 0.001), respectively. Using the score, the risk of MACE was 4.7, 10.7, 9.2 and 40% for scores 0, 1, 2 and 3 (p = 0.023), respectively. CONCLUSION: Preoperative transthoracic echocardiography identifies patients at risk of death or non-fatal cardiovascular events even late after renal transplantation. This suggests that echocardiography might be useful to identify patients requiring more aggressive long-term treatment of modifiable vascular risk factors.

Early left ventricular systolic function is a more sensitive predictor of adverse events after heart transplant.

BACKGROUND: First-phase ejection fraction (EF1) is a novel measure of early changes in left ventricular systolic function. This study was to investigate the prognostic value of EF1 in heart transplant recipients. METHODS: Heart transplant recipients were prospectively recruited at the Union Hospital, Wuhan, China between January 2015 and December 2019. All patients underwent clinical examination, biochemistry measures [brain natriuretic peptide (BNP) and creatinine] and transthoracic echocardiography. The primary endpoint was a combined event of all-cause mortality and graft rejection. RESULTS: In 277 patients (aged 48.6 ± 12.5 years) followed for a median of 38.7 [26.8-45.0] months, there were 35 (12.6%) patients had adverse events including 20 deaths and 15 rejections. EF1 was negatively associated with BNP (ß = -0.220, p < 0.001) and was significantly lower in patients with events compared to those without. EF1 had the largest area under the curve in ROC analysis compared to other measures. An optimal cut-off value of 25.8% for EF1 had a sensitivity of 96.3% and a specificity of 97.1% for prediction of events. EF1 was the most powerful predictor of events with hazard ratio per 1% change in EF1: 0.628 (95%CI: 0.555-0.710, p < 0.001) after adjustment for left ventricular ejection fraction and global longitudinal strain. CONCLUSIONS: Early left ventricular systolic function as measured by EF1 is a powerful predictor of adverse outcomes after heart transplant. EF1 may be useful in risk stratification and management of heart transplant recipients.

Decline in Left Ventricular Early Systolic Function with Worsening Kidney Function in Children with Chronic Kidney Disease: Insights from the 4C and HOT-KID Studies.

INTRODUCTION: Adults with childhood-onset chronic kidney disease (CKD) have an increased risk of cardiovascular disease. First-phase ejection fraction (EF1), a novel measure of early systolic function, may be a more sensitive marker of left ventricular dysfunction than other markers in children with CKD. OBJECTIVE: To examine whether EF1 is reduced in children with CKD. METHODS: Children from the 4C and HOT-KID studies were stratified according to estimated glomerular filtration rate (eGFR). The EF1 was calculated from the fraction of left ventricular (LV) volume ejected up to the time of peak aortic flow velocity. RESULTS: The EF1 was measured in children ages 10.9 ± 3.7 (mean ± SD) years, 312 with CKD and 63 healthy controls. The EF1 was lower, while overall ejection fraction was similar, in those with CKD compared with controls and decreased across stages of CKD (29.3% ± 3.7%, 23.5% ± 4.5%, 19.8% ± 4.0%, 18.5% ± 5.1%, and 16.7% ± 6.6% in controls, CKD 1, 2, 3, and ≥ 4, respectively, P < .001). The relationship of EF1 to eGFR persisted after adjustment for relevant confounders (P < .001). The effect size for association of measures of LV structure or function with eGFR (SD change per unit change in eGFR) was greater for EF1 (ß = 0.365, P < .001) than for other measures: LV mass index (ß = -0.311), relative wall thickness (ß = -0.223), E/e' (ß = -0.147), and e' (ß = 0.141) after adjustment for confounders in children with CKD. CONCLUSIONS: Children with CKD exhibit a marked and progressive decline in EF1 with falling eGFR. This suggests that EF1 is a more sensitive marker of LV dysfunction when compared to other structural or functional measures and that early LV systolic function is a key feature in the pathophysiology of cardiac dysfunction in CKD.

Polystyrene nanospheres-induced hepatotoxicity in swamp eel (Monopterus albus): From biochemical, pathological and transcriptomic perspectives.

As ubiquitous emerging pollutants, microplastics (MPs) in aquatic environments have aroused critical global concerns. Despite the occurrence and characteristics of MPs in freshwater agroecosystems well-described by our previous study, their ecotoxicological implications in Monopterus albus remains unfathomed. Herein, we dissected toxic effects and mechanisms of PS-NPs exposure against M. albus hepatic tissues at concentrations of 0.5 (L), 5 (M), 10 (H) mg/L for 28 days using physiochemical measurements, histopathological analysis and transcriptomic sequencing. Results showed that upon PS-NPs treatments, levels of ROS, MDA, 8-OHdG and MFO activity were significantly enhanced relative to the control (C) group, while SP content and T-AOC activity were dramatically suppressed, suggesting ROS burst, lipid peroxidation and DNA damage may occur in liver tissues. This oxidative damage further triggered impaired hepatic function and histopathology, disordered lipid metabolism and hepatocyte apoptosis, as reflected by significantly diminished activities of GPT, GOT, ACP, AKP and LDH, paralleled with augmented levels of TG, TC and HSI as well as Cytc and Caspase-3,8,9 activities. Noticeably, concentration-dependent rises of apoptotic rate, vacuolar degeneration and lipid deposition were manifest in TUNEL, H&E and ORO staining. In addition, a total of 375/475/981 up-regulated as well as 260/611/1422 down-regulated DEGs in C vs L, C vs M and C vs H categories were identified based on RNA-seq, respectively. These DEGs were significantly annotated and enriched into GO terms (membrane, cytoplasm, response to stimuli, oxidation-reduction process) as well as KEGG pathways (ether lipid metabolism, apoptosis, chemical carcinogenesis-reactive oxygen species, non-alcoholic fatty liver disease). Moreover, signaling cascades Keap1-Nrf2, p53 and PPAR were either substantially initiated or dysregulated to orchestrate PS-NPs hepatotoxicity featuring oxidative damage, hepatocyte apoptosis and lipid steatosis. Collectively, this study not only expounded on toxicological mechanisms whereby PS-MPs exerted deleterious effects on M. albus, but also pointed to ecological risks of PS-MPs-induced hepatoxicity and lipid steatosis in this commercially-important species.

Lactoferrin Relieves Deoxynivalenol-Induced Oxidative Stress and Inflammatory Response by Modulating the Nrf2/MAPK Pathways in the Liver.

Deoxynivalenol (DON), one of the most common mycotoxins contaminating food and feed, has been shown to induce hepatotoxicity. Lactoferrin (LF) enriched in human milk is a critical functional food component and performs the hepatoprotection function. Here, we aimed to explore whether dietary LF supplementation can protect from DON-induced hepatotoxicity and uncover the underlying mechanism in mice and alpha mouse liver 12 (AML12) hepatocytes. In vivo results revealed that LF alleviated DON-induced liver injury, reflected by repairing the hepatic histomorphology and decreasing the plasma alanine aminotransferase (ALT) level and the number of blood white blood cells (WBC) and neutrophils (Neu). Moreover, LF decreased the hepatic reactive oxygen species (ROS) and malondialdehyde (MDA) accumulation and enhanced the hepatic GSH-px activity and protein expression of Nrf2 and GPX4 to reverse the DON-induced hepatic oxidative stress. Furthermore, LF downregulated the pro-inflammatory-response-related gene expressions (IL1ß, TNFα, and Tlr4) and the phosphorylation levels of IKK, IκBα, and p38 in the liver of DON-exposed mice. Additionally, in vitro studies confirmed that LF ameliorated the DON-induced oxidation-reduction imbalance, inflammatory responses, and associated core modulators of the Nrf2 and MAPK pathways in DON-induced hepatotoxicity. In conclusion, LF performs hepatic antioxidative and anti-inflammatory functions by regulating the Nrf2/MAPK signaling pathways, thus reducing DON-induced hepatotoxicity.