Effects of reducing copper and zinc supplementation on the performance and mineral status of fattening pigs.

Pig manure with high copper (Cu) and zinc (Zn) concentration is applied to the soil, and these trace minerals can accumulate in the topsoil and decrease its fertility. Thus, adjusting concentrations of Cu and Zn in pig diets below current maximum allowance can prevent this risk. Reduction of dietary concentrations of Cu and Zn reduces their faecal excretion since only a small portion is retained in the pig's body. The aim of this study was to evaluate the effects of reducing concentration of dietary Cu and Zn or withdrawing their supplementation on the performance and mineral status of fattening pigs. Four dietary treatments were compared: a basal diet (WS; withdraw supplementation), with no Cu or Zn supplementation (5 and 29 mg/kg of native Cu and Zn, respectively); intermediate concentration (OINT), supplemented with Cu and Zn oxides to obtain mean dietary concentration of 7.4 and 47.5 mg/kg of Cu and Zn, respectively; and two diets supplemented with oxides (OREG) or sulphates (SREG) at concentration similar to European Union limits (i.e. 25 and 120 mg/kg of total Cu and Zn, respectively), as commonly used on commercial farms. Ninety-six pigs (24.3 ± 3.3 kg BW) were each assigned to one of the four treatments and reared in individual pens for 14 weeks (up to 110.3 ± 8.9 kg BW). Animal performances were measured, and samples of plasma (on day 1 and day 41 of experimentation and at slaughter), bones and the liver (at slaughter) were collected from all pigs. Faecal samples were collected from all pigs every 3 weeks to determine the Cu and Zn excretion. Over the entire experiment, neither the concentration nor the source of Cu and Zn influenced feed intake, BW or the feed conversion ratio. Plasma Cu and Zn concentrations were not influenced by the treatment but increased as the age of the pigs increased. Liver Cu concentration increased (P < 0.05) as dietary concentrations increased (OREG> WS). Neither the concentration nor the source of Cu and Zn influenced bone Cu and Zn concentration or physical bone parameters. However, SREG had a higher maximum load until bone breaking (P < 0.05) than OREG. As expected, faecal excretion of Cu and Zn decreased (P < 0.01) as dietary concentration decreased. Dietary Cu and Zn can be reduced without decreasing the performance or mineral status of pigs, and these results should be validated on commercial farms that have more challenging health conditions.

Anti-cancer agent 5-fluorouracil reverses meropenem resistance in carbapenem-resistant Gram-negative pathogens.

The global increasing incidence of clinical infections caused by carbapenem-resistant Gram-negative pathogens demands urgent and effective treatment strategies. Antibiotic adjuvants represent a promising approach to enhance the efficacy of meropenem against carbapenem-resistant bacteria. Herein, we identified the anticancer agent 5-fluorouracil (5-FU, 50 µM) significantly reduced the minimal inhibitory concentration of meropenem against blaNDM-5 positive Escherichia coli by 32-fold through cell-based high-throughput screening. Further pharmacological studies indicated that 5-FU exhibited the potentiation effects on carbapenem antibiotics against 42 Gram-negative bacteria producing either metallo-ß-lactamases (MBLs), such as NDM and IMP, or serine ß-lactamases (Ser-BLs), like KPC and OXA. These bacteria included E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa and Acinetobacter spp., with 32 of them obtained from human clinical samples. Mechanistic investigations revealed that 5-FU inhibited the transcriptional and expressional level of the blaNDM-5 gene. Additionally, the 5-FU combined with meropenem can enhance bacterial metabolism, and stimulate the production of Reactive Oxygen Species (ROS), thereby rendering bacteria more susceptible to meropenem. This drug combination could effectively elevate the survival rate from 16.7% to 83.3% compared to meropenem monotherapy, and reduce bacteria loads in tissues in a mouse systemic infection model. Collectively, these findings reveal that the potential of 5-FU as a novel meropenem adjuvant to improve treatment outcomes against carbapenem-resistant bacteria infections.

Sex disparity in the association between metabolic-anthropometric phenotypes and risk of obesity-related cancer: a prospective cohort study.

BACKGROUND: Sex disparity between metabolic-obesity (defined by body mass index, BMI) phenotypes and obesity-related cancer (ORC) remains unknown. Considering BMI reflecting overall obesity but not fat distribution, we aimed to systematically assess the association of our newly proposed metabolic-anthropometric phenotypes with risk of overall and site-specific ORC by sex. METHODS: A total of 141,579 men (mean age: 56.37 years, mean follow-up time: 12.04 years) and 131,047 women (mean age: 56.22 years, mean follow up time: 11.82 years) from the UK Biobank was included, and designated as metabolic-anthropometric phenotypes based on metabolic status (metabolically healthy/unhealthy), BMI (non-obesity/obesity) and body shape (pear/slim/apple/wide). The sex-specific association of different phenotypes with overall and site-specific ORC was assessed by hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox proportional hazards regression models. RESULTS: We found metabolically unhealthy and/or obesity phenotypes conveyed a higher risk in men than in women for overall ORC and colorectal cancer compared with metabolically healthy non-obesity phenotype (Pinteraction < 0.05). Of note, metabolically healthy obesity phenotype contributed to increased risks of most ORC in men (HRs: 1.58 ~ 2.91), but only correlated with higher risks of endometrial (HR = 1.89, 95% CI: 1.54-2.32) and postmenopausal breast cancers (HR = 1.17, 95% CI: 1.05-1.31) in women. Similarly, even under metabolically healthy, men carrying apple and wide shapes phenotypes (metabolically healthy apple/wide and metabolically healthy non-obesity apple/wide) suffered an increased risk of ORC (mainly colorectal, liver, gastric cardia, and renal cancers, HRs: 1.20 ~ 3.81) in comparison with pear shape or non-obesity pear shape. CONCLUSIONS: There was a significant sex disparity between metabolic-anthropometric phenotypes and ORC risk. We advised future ORC prevention and control worth taking body shape and sex disparity into account.

Effects of Bacillus subtilis on Growth Performance, Metabolic Profile, and Health Status in Dairy Calves.

This study focused on assessing whether the inclusion of probiotics (B. subtilis) as feed additives during the preweaning stage can enhance the body weight and metabolic condition of neonatal calves. A total of 50 Holstein calves, all born on the same farm, were randomly divided into two homogeneous treatment groups after birth. The calves in the control group (CG) were fed a milk replacer (n = 25) (13 females and 12 males) and those in the B. subtilis-supplement-treated group (TG), (n = 25) (13 females and 12 males) were fed a milk replacer with 7.5 mL/calf/day of B. subtilis probiotic (complied with the manufacturer's guidelines). The probiotic was administered 24 h post-birth, signifying the start of the experimental period. It took one month to collect the animals. Body weight was measured at birth for all animals. A local veterinarian, working on the farm, conducted daily health checks of the calves, recording health parameters and any antibiotic treatments. Blood samples were collected from each calf at birth and 30, 60, and 90 days by puncturing the jugular vein using 10 mL evacuated serum tubes before morning feeding. Significant differences in body weight were observed between the CG and the TG at 30, 60, and 90 days of age. At 30 days, the TG had a 4.11% higher average body weight than the CG (54.38 kg vs. 52.71 kg). At 60 days, the TG's average weight was 3.75% higher (79.21 kg vs. 76.34 kg), and at 90 days, the TG had a 2.91% higher average weight (112.87 kg vs. 109.67 kg). At 30 days of age, the TG showed significantly lower AST activity, with a 41.12% decrease compared to the CG (51.02 IU/L vs. 72.00 IU/L). Conversely, GGT activity was significantly higher in the TG by 64.68% (40.64 IU/L vs. 14.35 IU/L). Phosphorus concentration at 30 days was also significantly higher in the TG by 9.36% (3.27 mmol/L vs. 2.99 mmol/L). Additionally, the TG had a significantly lower total protein concentration, with a 21.63% decrease at 30 days (46.32 g/L vs. 56.34 g/L) and a 20.28% decrease at 60 days (48.32 g/L vs. 58.12 g/L) compared to the CG. These findings indicate that dairy calves given conventional milk replacer along with a daily dose of 7.5 mL of B. subtilis probiotic experienced enhanced growth performance and a more favourable metabolic profile during the first 90 days of their lives.

Influence of myo-inositol on metabolic status for gestational diabetes: a meta-analysis of randomized controlled trials.

INTRODUCTION: The efficacy of myo-inositol supplementation to treat gestational diabetes remains controversial, and this meta-analysis aims to study the efficacy of myo-inositol supplementation on metabolic status for gestational diabetes. METHODS: Several databases including PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases were systemically searched from inception to October 2021, and we included the randomized controlled trials (RCTs) assessing the effect of myo-inositol supplementation on the outcomes of women with gestational diabetes. Gestational diabetes was diagnosed if at least one threshold of glucose concentration was exceeded and the three thresholds included 92, 180, and 153 mg/dl for 0, 1 and 2 h, respectively, after a 75-g, 2-h glucose tolerance test. RESULTS: Four RCTs and 317 patients were included in this meta-analysis. Compared with routine treatment in pregnant women with gestational diabetes, myo-inositol supplementation could lead to remarkably decreased treatment requirement with insulin (odd ratio [OR] = 0.24; 95% confidence interval [CI] = 0.11-0.52; p = .0003) and homeostasis model assessment of insulin resistance (HOMA-IR, standard mean difference [SMD]= -1.18; 95% CI= -1.50 to -0.87; p < .00001), but demonstrated no obvious impact on birth weight (SMD= -0.11; 95% CI= -0.83 to 0.61 g; p = .76), cesarean section (OR = 0.82; 95% CI = 0.46-1.47; p = .51) or the need of NICU (OR = 0.88; 95% CI = 0.03-26.57; p = .94). CONCLUSIONS: Myo-inositol supplementation is effective to decrease the need of insulin treatment and HOMA-IR for gestational diabetes.

Association between IGF-1 and IGFBPs in Blood and Follicular Fluid in Dairy Cows Under Field Conditions.

Insulin-like growth factor 1 (IGF-1) regulates dairy cow reproduction, while the paracrine IGF system locally influences fertility. In both systems, IGF-1 bioactivity is regulated through binding proteins (IGFBPs) inhibiting IGF-1 binding to its receptor (IGF1R). This study aimed to investigate a possible transfer between this endocrine and paracrine system. Therefore, blood and follicular fluid (FF) from postpartum dairy cows were analysed for ß-hydroxybutyrate (BHB), IGF-1, IGFBP-2, -3, -4, -5, and an IGFBP fragment in two study parts. The mRNA expression of IGFBP-2, IGFBP-4, IGF1R, and the pregnancy-associated plasma protein A (PAPP-A) in granulosa cells was measured. The results showed correlations between plasma and FF for IGF-1 (r = 0.57, p < 0.001) and IGFBP-2 (r = -0.57, p < 0.05). Blood BHB negatively correlated with IGF-1 in blood and FF and IGFBP-3, -5 and total IGFBP in blood (IGF-1 plasma: r = -0.26, p < 0.05; FF: r = -0.35, p < 0.05; IGFBP-3: r = -0.64, p = 0.006; IGFBP-5: r = -0.49, p < 0.05; total IGFBP: r = -0.52, p < 0.05). A negative correlation was found between IGFBP-2 expression and IGF-1 concentration in FF (r = -0.97, p = 0.001), while an IGFBP fragment positively correlated with IGF1R-mRNA in FF (r = 0.82, p = 0.042). These findings suggest a transfer and local regulation between the somatotropic axis and the follicular IGF system, linking the metabolic status with local effects on dairy cow fertility.

Prepartum anti-inflammatory therapies in Holstein dairy cows blocked by parity and body condition score group: Effects on metabolic stress, systemic inflammation, performance, and health.

The objective of this study was to assess the effects of prepartum administration of anti-inflammatory therapies on body condition score (BCS), ß-hydroxybutyrate (BHB) concentration, haptoglobin (HP) concentration, milk yield, milk components, rumination time, clinical health events and reproductive performance in Holstein dairy cows. At 14 d before the expected calving date, cows (PAR; n = 170) and heifers (nulliparous [NUL]; n = 63) were blocked by BCS group (optimal = 3-3.5 [OPT]; over-conditioned cows [OVERC; BCS ≥ 3.75 pts.]) and parity (NUL; PAR) and randomly allocated to one of 3 treatment groups: 1) ASA (n = 78): receive one oral administration of acetylsalicylic acid (4 boluses; 480 grain/bolus); 2) MEL (n = 76): receive one oral administration with meloxicam (1mg/kg of BW), or 3) PLC (n = 77): receive one oral treatment with gelatin capsules filled with water. Body condition score was assessed, and blood samples were collected, weekly starting one week before treatment until 3 weeks after calving. Daily milk yields and daily rumination times were collected from on-farm computer records. Dairy Herd Improvement Association (DHIA) monthly test data were collected to assess milk yield, somatic cell counts, and milk components. Furthermore, health events, culling rate, and reproductive performance data were collected from on-farm computer records. The data were analyzed using MIXED, GLIMMIX, and LIFETEST procedures of SAS as a randomized complete block design. On average, MEL-NUL cows produced 4.77 ± 0.93 kg/d and 4.81 ± 0.92 kg/d more milk from wk 6 to wk 21 of lactation compared with ASA-NUL and PLC-NUL cows, respectively. Similarly, there was a week by treatment by body condition group interaction (P = 0.01), where OVERC cows treated with MEL produced more milk from wk 10 to wk 15 of lactation compared with ASA- OVERC and PLC-OVERC cows. Parous cows treated with ASA had lower BCS compared with PAR cows treated with MEL or PLC. A lower percentage of OVERC cows treated with ASA became sick in the first 60 DIM compared with MEL- OVERC and PLC- OVERC cows (ASA = 23.88 ± 7.26%, MEL = 46.36 ± 8.57%; PLC = 46.74 ± 8.53%; P = 0.04). Parous cows treated with ASA had (P = 0.03) a higher hazard ratio to become pregnant by 300 DIM compared with PAR MEL cows. Although the study was not sized for finding treatment differences in blocking criteria groups, these results suggest that treatment with prepartum anti-inflammatory therapies may have positive effects on milk yield and postpartum health in specific groups of cows, such as NUL and OVERC cows, while it may not be recommended for other animal categories, such as parous cows and cows with optimal BCS. Larger studies are needed to strengthen the associations observed in this study.

Major depletion of insulin sensitivity-associated taxa in the gut microbiome of persons living with HIV controlled by antiretroviral drugs.

BACKGROUND: Persons living with HIV (PWH) harbor an altered gut microbiome (higher abundance of Prevotella and lower abundance of Bacillota and Ruminococcus lineages) compared to non-infected individuals. Some of these alterations are linked to sexual preference and others to the HIV infection. The relationship between these lineages and metabolic alterations, often present in aging PWH, has been poorly investigated. METHODS: In this study, we compared fecal metagenomes of 25 antiretroviral-treatment (ART)-controlled PWH to three independent control groups of 25 non-infected matched individuals by means of univariate analyses and machine learning methods. Moreover, we used two external datasets to validate predictive models of PWH classification. Next, we searched for associations between clinical and biological metabolic parameters with taxonomic and functional microbiome profiles. Finally, we compare the gut microbiome in 7 PWH after a 17-week ART switch to raltegravir/maraviroc. RESULTS: Three major enterotypes (Prevotella, Bacteroides and Ruminococcaceae) were present in all groups. The first Prevotella enterotype was enriched in PWH, with several of characteristic lineages associated with poor metabolic profiles (low HDL and adiponectin, high insulin resistance (HOMA-IR)). Conversely butyrate-producing lineages were markedly depleted in PWH independently of sexual preference and were associated with a better metabolic profile (higher HDL and adiponectin and lower HOMA-IR). Accordingly with the worst metabolic status of PWH, butyrate production and amino-acid degradation modules were associated with high HDL and adiponectin and low HOMA-IR. Random Forest models trained to classify PWH vs. control on taxonomic abundances displayed high generalization performance on two external holdout datasets (ROC AUC of 80-82%). Finally, no significant alterations in microbiome composition were observed after switching to raltegravir/maraviroc. CONCLUSION: High resolution metagenomic analyses revealed major differences in the gut microbiome of ART-controlled PWH when compared with three independent matched cohorts of controls. The observed marked insulin resistance could result both from enrichment in Prevotella lineages, and from the depletion in species producing butyrate and involved into amino-acid degradation, which depletion is linked with the HIV infection.

How General and Inflammatory Status Impacts on the Prognosis of Patients Affected by Lung Cancer: State of the Art.

Pulmonary cancer is often associated with systemic inflammation and poor nutritional status and these two aspects are strongly correlated and related to the scarce infiltration of a tumor by immune cells. We reviewed all English literature reviews from 2000 to 2024 from PubMed, Scopus and Google Scholar, including original articles, review articles, and metanalyses. We excluded non-English language articles and case reports/case series. Generally speaking, nutritional and inflammatory status largely affect medium and long-term prognosis in lung cancer patients. A correct stratification of patients could improve their preoperative general functional nutritional and inflammatory status, minimizing, therefore, possible treatment complications and improving long-term prognosis.

The effects of probiotics supplements on metabolic indices and clinical signs in patients with diabetic retinopathy, a randomized double blind clinical trial.

Purpose: This study was carried out to evaluate the effects of probiotics administration on clinical status and metabolic profiles in diabetic retinopathy (DR) patients. Methods: This randomized, double-blind, placebo-controlled trial was conducted among 72 DR patients. Subjects received probiotics including Lactobacillus acidophilus, Bifidobacterium bifidum, Bifidobacterium langum, Bifidobacterium lactis daily (2 × 109 CFU/each strain) (n = 36) or placebo (starch) (n = 36) and were instructed to take one capsule daily for 12 weeks. Finally, 55 participants [probiotic group (n = 30) and placebo group (n = 25)] completed the study. Fasting blood samples were obtained at baseline and after the 12-week intervention to determine metabolic profiles. To determine the effects of probiotic supplementation on clinical symptoms and biochemical variables, we used one-way repeated measures analysis of variance. Results: After the 12-week intervention, compared with the placebo, probiotic supplementation significantly decreased means serum insulin concentrations (Probiotic group: -4.9 ± 6.5vs. Placebo group: 3.0 ± 7.7 µIU/mL, Ptime×group<0.001), homeostatic model assessment for insulin resistance (Probiotic group: -2.5 ± 3.8 vs. Placebo group: 1.1 ± 2.7, Ptime×group<0.001) and hemoglobin A1c (HbA1C) (Probiotic group: -0.4 ± 0.7 vs. Placebo group: -0.02 ± 0.2%, Ptime×group=0.01), and significantly increased the quantitative insulin sensitivity check index (QUICKI) (Probiotic group: 0.02 ± 0.03 vs. Placebo group: -0.03 ± 0.04, Ptime×group<0.001). There was no significant effect of probiotic administration on other metabolic profiles and clinical symptoms. Conclusions: Overall, probiotic supplementation after 12 weeks in DR patients had beneficial effects on few metabolic profiles. This study was registered under the Iranian website for clinical trials as http://www.irct.ir: IRCT20130211012438N29.

Metabolic Clusters of Early-Lactating Dairy Cows Based on Blood ß-hydroxybutyrate Trajectories and Predicted from Milk Compounds.

High-yielding dairy cows encounter metabolic challenges in early lactation. Typically, ß-hydroxybutyrate (BHB), measured at a specific time point is employed to diagnose the metabolic status of cows based on a predetermined threshold. However, in early lactation, BHB is highly dynamic, and there is high interindividual variability in its time profile. This could limit the effectiveness of the single measurement and threshold-based diagnosis probably contributing to the disparities in reports linking metabolic status with productive and reproductive outcomes. This research delves into the examination of the trajectories of BHB to unveil inter-cow variations and identify latent metabolic groups. We compiled a data set from 2 observational studies involving a total of 195 lactations from multiparous Holstein Friesian cows. The data set encompasses measurements of BHB, NEFA, and insulin from blood samples collected at 3, 6, 9, and 21 d in milk (DIM), along with weekly determinations of milk composition and fatty acids (FA) proportions in milk fat. In both experiments, milk yield (MY) and feed intake were recorded daily during the first month of lactation. We explored interindividual and intraindividual variations in metabolic responses using the trajectories of blood BHB and evaluated the presence of distinct metabolic groups based on such variations. For this purpose, we employed the growth mixture model (GMM), a trajectory clustering technique. Our findings unveil novel insights into the diverse metabolic responses among cows, encompassing both trajectory patterns and the magnitude of blood BHB concentrations. Specifically, we identified 3 latent metabolic groups: the "QuiBHB" cluster (≈10%) exhibited a higher initial BHB concentration than other clusters, peaking on d 9 (average maximum BHB of 2.4 mM) and then declining by d 21; the "SloBHB" cluster (≈23%) started with a lower BHB concentration, gradually increasing until d 9, and at the highest BHB concentration at d 21 (1.6 mM serum BHB at the end of the experimental period); and the "LoBHB" cluster (≈67%) began with the lowest serum BHB concentration (serum BHB <0.75 mM), remaining relatively stable throughout the sampling period. Notably, the 3 metabolic groups exhibited significant physiological disparities, evident in blood NEFA and insulin concentrations. The QuiBHB and SloBHB cows exhibited higher NEFA and lower insulin concentrations as compared with the LoBHB cows. Interestingly, these metabolic differences extended to MY and DMI during the first month of lactation. The elevated BHB concentrations observed in QuiBHB cows were linked with lower DMI and MY as compared with SloBHB and LoBHB cows. Accordingly, these animals were considered metabolically impaired. Conversely, SloBHB cows displayed higher MY along with increased DMI, and thus the elevated BHB might be indicative of an adaptive response for these cows. The QuiBHB cows also displayed higher proportions of unsaturated FA (UFA), monounsaturated FA (MUFA), and total C18:1 FA in milk during the first week of lactation. Prediction of the QuiBHB cows using these FA and test day variables resulted in moderate predictive accuracy (ROCAUC > 0.7). Given the limited sample size for the development of prediction models, and the variation in DIM among samples in the same week, the result is indicative of the predictive potential of the model and room for model optimization. In summary, distinct metabolic groups of cows could be identified based on the trajectories of blood BHB in early lactation.

Systemic inflammation in early lactation and its relation to the cows' oxidative and metabolic status, productive and reproductive performance, and activity.

A dysregulated inflammatory response contributes to the occurrence of disorders in cows during the transition period from pregnancy to lactation. However, a detailed characterization of clinically healthy cows that exhibit an enhanced inflammatory response during this critical period remains incomplete. In this experiment, a total of 99 individual transition dairy cows and 109 observations (18 cows monitored in 2 consecutive lactations), submitted to similar transition management were involved to evaluate the relationship between elevated an inflammatory response and metabolic and oxidative status, as well as transition outcomes. Blood was taken at -7, 3, 6, 9, and 21 DIM, and concentrations of metabolic parameters (glucose, ß-hydroxybutyric acid, nonesterified fatty acids [NEFA], insulin, IGF-1, and fructosamine) were analyzed. Additionally, oxidative parameters (proportion of oxidized glutathione to total glutathione in red blood cells, the activity of glutathione peroxidase [GPx] and superoxide dismutase, concentrations of malondialdehyde, and oxygen radical absorbance capacity) and acute phase proteins (APP) including haptoglobin (Hp), serum amyloid A (SAA) and albumin-to-globulin ratio (A:G) were determined in the blood at 21 DIM. The 3 APP parameters were used to group clinically healthy cows into 2 categories through k-medoids clustering (i.e., a group showing an acute phase response, APR; n = 39) and a group not showing such a response (i.e., non-APR; n = 50). Diseased cases (n = 20) were handled in a separate group. Lower SAA and Hp concentrations as well as higher A:G were observed in the non-APR group, although for Hp, differences were observed from the APR group and not from the diseased group. Only 1 of the 5 oxidative parameters differed between the groups, with the non-APR group exhibiting lower GPx activity compared with the diseased group. The non-APR group showed the highest IGF-1 levels among the 3 groups and and lower NEFA concentrations compared with the diseased groups. Cows in the diseased group also showed reduced dry matter intake and milk yield compared with clinically healthy cows, regardless of their inflammatory status. Moreover, the APR group exhibited temporarily lower activity levels compared with the non-APR group. These findings highlight that cows with a lower inflammatory status after 21 DIM exhibited better metabolic health characteristics and productive performance, as well as activity levels. Nevertheless, the detrimental effects of a higher inflammatory status in the absence of clinical symptoms are still relatively limited.

Dietary phytosterols improves the metabolic status of perinatal cows as evidenced by plasma metabolomics and faecal microbial metabolism.

OBJECTIVE: Previous research reported that dietary addition with phytosterols improved the energy utilisation of the rumen microbiome, suggesting its potential to alleviate the negative energy balance of perinatal cows. This experiment aimed to explore the effects of feeding phytosterols on the metabolic status of perinatal cows through plasma metabolomics and faecal bacteria metabolism. METHODS: Ten perinatal Holstein cows (multiparous, 2 parities) with a similar calving date were selected four weeks before calving. After 7 days for adaptation, cows were allocated to two groups (n = 5), which respectively received the basal rations supplementing commercial phytosterols at 0 and 200 mg/d during a 42-day experiment. The milk yield of each cow was recorded daily after calving. On days 1 and 42, blood and faeces samples were all collected from perinatal cows before morning feeding for analysing plasma biochemicals and metabolome, and faecal bacteria metabolism. RESULTS: Dietary addition with phytosterols at 200 mg/d had no effects on plasma cholesterol and numerically increased milk yield by 1.82 kg/d (p>0.10) but attenuated their negative energy balance in perinatal cows as observed from the significantly decreased plasma level of ß-hydroxybutyric acid (p = 0.002). Dietary addition with phytosterols significantly altered 12 and 15 metabolites (p<0.05) within the plasma and faeces of perinatal cows, respectively. Of these metabolites, 5 upregulated plasma fatty acids indicated an improved energy status (i.e., C18:1T, C14:0, C17:0, C18:0, and C16:0). Milk yield negatively correlated with plasma concentrations of ketone bodies (p = 0.035) and 5-methoxytryptamine (p = 0.039). Furthermore, dietary addition with phytosterols at 200 mg/d had no effects on fermentation characteristics and bacterial diversity of cow faeces (p>0.10) but improved potentially beneficial bacteria such as Christensenellaceae family (p<0.05) that positively correlated with feed efficiency. CONCLUSION: Dietary addition with phytosterols at 200 mg/d could effectively improve the energy status in perinatal cows by attenuating their negative energy balance.

Dry period length affects rumen adaptation in dairy cattle precalving and during the first weeks after calving.

Omitting or shortening the dry period may result in a fairly constant ration throughout the transition period of dairy cows, reducing the need for adaptation of cow metabolism and rumen function to a new lactation. The objective of this study was to determine the effect of dry period length (DP) on rumen adaptation and cow metabolic state during the transition period. Twelve pregnant, rumen-cannulated Holstein Friesian dairy cows at the end of their first lactation were assigned to 1 of 3 treatments: a conventional (60 d), short (30 d), or no dry period (0 d). At dry-off, cows received a dry-cow ration until calving. Lactating cows received a lactation ration. Cows were monitored from 8 wk before calving until 8 wk after calving for milk yield and DMI. Rumen biopsies were taken from 3 locations in the rumen at 60, 40, and 10 d before calving and 3, 7, 14, 28, and 56 d after calving to assess papillae dimensions. Blood was sampled weekly from 3 wk before until 8 wk after calving, and liver biopsies were taken at wk -2, 2, and 4 relative to calving. Prepartum, DMI, and milk yield were greater for cows with a short or no dry period, compared with cows with a conventional dry period. Postpartum, DMI was greater for cows with a short dry period compared with cows with a conventional dry period. Plasma glucose concentration was greater for cows without a dry period, compared with the other DP postpartum. Plasma concentrations of nonesterified fatty acids and BHB, and liver triglyceride content, did not differ among dry period. Rumen papillae differed in size based on biopsy location, but there was no interaction between biopsy location and the effect of DP. Rumen papillae surface area for cows managed for a 30- or 60-d dry period decreased toward calving. At 40 d prepartum, papillae surface area was greater for short and no dry period treatment compared with a conventional dry period. At 10 d prepartum, papillae surface area was greater for the no dry period treatment compared with both other treatments, and this difference was still present 3 d postpartum. Cows managed for a short dry period showed faster increase in papillae dimensions after calving compared with cows managed for a conventional dry period. From d 28 onwards, no differences in papillae surface area were observed. The faster rumen adaptation postpartum may be related to the increased DMI during the first weeks postpartum for cows managed for a short dry period. However, this did not result in improved metabolic status or milk yield. The results from the present study demonstrate that the dietary changes related to a conventional DP affected rumen papillae development, not only prepartum but also early postpartum. Further optimization of DP as well as dietary composition throughout the transition period may support cows in their adaptation to a new lactation.

Galectin-3, Metabolic Risk, and Incident Heart Failure: The ARIC Study.

BACKGROUND: It is unclear how metabolic syndrome (MetS) and diabetes affect Gal-3 (galectin 3) levels and the resulting implications for heart failure (HF) risk. We assessed relationships of MetS and diabetes with Gal-3, and their joint associations with incident HF. METHODS AND RESULTS: We included 8445 participants without HF (mean age, 63 years; 59% men; 16% Black race) at ARIC (Atherosclerosis Risk in Communities) study visit 4 (1996-1999). We categorized participants as having MetS only, MetS with diabetes, or neither, and by quartiles of MetS severity Z score. We assessed cross-sectional associations of metabolic risk categories with high Gal-3 level (≥75th percentile) using logistic regression. We used Cox regression to evaluate combined associations of metabolic risk categories and Gal-3 quartiles with HF. In cross-sectional analyses, compared with no MetS and no diabetes, MetS only (odds ratio [OR], 1.24 [95% CI, 1.10-1.41]) and MetS with diabetes (OR, 1.59 [95% CI, 1.32-1.92]) were associated with elevated Gal-3. Over a median follow-up of 20.5 years, there were 1749 HF events. Compared with individuals with neither diabetes nor MetS and with Gal-3 in the lowest quartile, the combination of MetS with diabetes and Gal-3 ≥75th percentile was associated with a 4-fold higher HF risk (hazard ratio, 4.35 [95% CI, 3.30-5.73]). Gal-3 provided HF prognostic information above and beyond MetS, NT-proBNP (N-terminal pro-B-type natriuretic peptide), high-sensitivity cardiac troponin T, and CRP (C-reactive protein) (ΔC statistic for models with versus without Gal-3: 0.003; P=0.004). CONCLUSIONS: MetS and diabetes are associated with elevated Gal-3. The HF risk significantly increased with the combination of greater metabolic risk and higher Gal-3.

Body size, insulin sensitivity, metabolic health and risk of cardiovascular disease in Chinese adults: Insights from the China Cardiometabolic Disease and Cancer Cohort (4C) study.

AIMS: To assess the excess risk of cardiovascular disease (CVD) associated with different criteria for metabolic health, and the interplay of body size, insulin sensitivity and metabolic health with CVD risk. MATERIALS AND METHODS: We conducted a prospective study involving 115 638 participants from the China Cardiometabolic Disease and Cancer Cohort (4C) Study. Metabolic health was defined using three different definitions: (1) insulin sensitivity defined by homeostatic model assessment of insulin resistance index; (2) absence of metabolic syndrome according to the National Cholesterol Education Program Adult Treatment Panel III criteria; and (3) simultaneous absence of metabolic abnormalities (diabetes, hypertension, dyslipidaemia). The primary endpoint was a composite of incident CVD events comprising the first occurrence of myocardial infarction, stroke, heart failure, or cardiovascular death. RESULTS: During a mean 3.61-year follow-up period, obese individuals with insulin sensitivity (multivariable-adjusted hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.37-2.08), or without metabolic syndrome (HR 1.46, 95% CI 1.13-1.89) still exhibited increased CVD risks, when compared to their normal-weight counterparts. Otherwise, those with obesity but simultaneous absence of metabolic abnormalities demonstrated similar CVD risk compared to normal-weight individuals (HR 0.91, 95% CI 0.53-1.59). CVD risk increased with the number of abnormalities across body mass index categories, regardless of insulin sensitivity. CONCLUSIONS: This study emphasizes the need for refined definitions of metabolic health and advocates for meticulous screening for metabolic abnormalities to reduce cardiovascular risks, even in individuals with normal weight and insulin sensitivity.

Single-cell RNA-seq reveals the metabolic status of immune cells response to immunotherapy in triple-negative breast cancer.

Immune checkpoint blockade (ICB) therapy offers promise in the treatment of triple-negative breast cancer (TNBC); however, its limited efficacy in certain TNBC patients poses a challenge. In this study, we elucidated the metabolic mechanism at 'sub-subtype' resolution underlying the non-response to ICB therapy in TNBC. Here, an analytic pipeline was developed to reveal the metabolic heterogeneity, which is correlated with the ICB outcomes, within each immune cell subtype. First, we identified metabolic 'sub-subtypes' within certain cell subtypes, predominantly T cell subsets, which are enriched in ICB non-responders and named as non-responder-enriched (NR-E) clusters. Notably, most of NR-E T metabolic cells exhibit globally higher metabolic activities compared to other cells within the same individual subtype. Further, we investigated the extra-cellular signals that trigger the metabolic status of NR-E T cells. In detail, the prediction of cell-to-cell communication indicated that NR-E T cells are regulated by plasmatic dendritic cells (pDCs) through TNFSF9, as well as by macrophages expressing SIGLEC9. In addition, we also validate the communication between TNFSF9+ pDCs and NR-E T cells utilizing deconvolution of spatial transcriptomics analysis. In summary, our research identified specific metabolic 'sub-subtypes' associated with ICB non-response and uncovered the mechanisms of their regulation in TNBC. And the proposed analytical pipeline can be used to examine metabolic heterogeneity within cell types that correlate with diverse phenotypes.

Is metabolic-healthy obesity associated with risk of dementia? An age-stratified analysis of the Whitehall II cohort study.

BACKGROUND: Metabolically healthy obesity is hypothesized to be a benign condition but whether this is the case for dementia remains debated. We examined the role of age at assessment of metabolic-obesity phenotypes in associations with incident dementia. METHODS: Obesity (body mass index ≥ 30 kg/m2) and poor metabolic health (≥ 2 of elevated serum triglycerides, low HDL-C, elevated blood pressure, and elevated serum fasting glucose) were used to define four metabolic-obesity phenotypes (metabolically healthy (MHNO) and unhealthy non-obesity (MUNO), metabolically healthy (MHO) and unhealthy obesity (MUO)) at < 60, 60 to < 70, and ≥ 70 years using 6 waves of data from the Whitehall II study and their associations with incident dementia was examined using Cox regression. RESULTS: Analyses with exposures measured < 60, 60 to < 70, and ≥ 70 years involved 410 (5.8%), 379 (5.6%), and 262 (7.4%) incident dementia cases over a median follow-up of 20.8, 10.3, and 4.2 years respectively. In analyses of individual components, obesity before 60 years (HR 1.41, 95% CI: [1.08, 1.85]) but not at older ages was associated with dementia; unhealthy metabolic status when present < 60 years (HR 1.33, 95% CI: [1.08, 1.62]) and 60 to < 70 years (HR 1.32, 95% CI: [1.07, 1.62]) was associated with dementia. Compared to the metabolically healthy non-obesity group, the risk of dementia was higher in those with metabolically healthy obesity before 60 years (1.69; 95% CI: [1.16, 2.45]); this was not the case when metabolic-obesity phenotype was present at 60 to < 70 years or ≥ 70 years. Analyses at older ages were on smaller numbers due to death and drop-out but inverse probability weighting to account for missing data yielded similar results. CONCLUSIONS: Individuals with metabolically healthy obesity before age 60 had a higher risk of incident dementia over a 27-year follow-up; the excess risk dissipates when metabolic health and obesity are measured after 70 years.

Age-Related Shift in Cardiac and Metabolic Phenotyping Linked to Inflammatory Cytokines and Antioxidant Status in Mice.

Age-related alterations in cardiac function, metabolic, inflammatory and antioxidant profiles are associated with an increased risk of cardiovascular mortality and morbidity. Here, we examined cardiac and metabolic phenotypes in relation to inflammatory status and antioxidant capacity in young, middle-aged and old mice. Real-time reverse transcription-polymerase chain reactions were performed on myocardium and immunoassays on plasma. Left ventricular (LV) structure and function were assessed by echocardiography using high-frequency ultrasound. Middle-aged mice exhibited an altered metabolic profile and antioxidant capacity compared to young mice, whereas myocardial expression of inflammatory factors (TNFα, IL1ß, IL6 and IL10) remained unchanged. In contrast, old mice exhibited increased expression of inflammatory cytokines and plasma levels of resistin compared to young and middle-aged mice (p < 0.05). The pro-inflammatory signature of aged hearts was associated with alterations in glutathione redox homeostasis and elevated contents of 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation and oxidative stress. Furthermore, echocardiographic parameters of LV systolic and diastolic functions were significantly altered in old mice compared to young mice. Taken together, these findings suggest age-related shifts in cardiac phenotype encompass the spectrum of metabo-inflammatory abnormalities and altered redox homeostasis.

Effects of early weaning on the reproductive performance of suckled Nelore cows in the subsequent breeding season.

This study aimed to evaluate the effects of early weaning (EW) on body composition, hormone concentrations and metabolites, and reproductive performance of Nelore cows in the subsequent breeding season (BS). Suckled cows that became pregnant by timed-AI (TAI) in the 2020-BS were exposed in 2021 to early weaning at 150 d (27 primiparous [PRI] and 74 multiparous [MUL]) or conventional weaning (CW) at 240 d postpartum (30 PRI and 77 MUL). Body weight (BW) and body condition score (BCS) were determined at 2020-BS, EW, CW, prepartum, and 2021-BS. Blood samples were collected at EW, CW, prepartum (54.75 ±â€…0.56 d prepartum), and 2021-TAI and assayed for insulin-like growth factor-1 (IGF-I), non-esterified fatty acid (NEFA), and ß-hydroxybutyrate (BHB) concentrations. In 2021-BS, cows were exposed to a P4/E2-based protocol for TAI at day 0 (D0), and a second TAI was performed at D22 in females detected with luteolysis (D20) by Doppler ultrasound. The presence of corpus luteum (CL) on D10, estrous expression, and dominant follicle (DF) diameter, and blood perfusion (BP) on D2 and D0 were determined. Data were analyzed by ANOVA or logistic regression of SAS as a 2 × 2 factorial with main factors of parity (PRI or MUL) and weaning strategy (EW or CW). An interaction of parity and weaning strategy was not observed (P > 0.1), but the weight (kg) and BCS were greater (P < 0.05) in MUL cows at the five timepoints, and EW cows were heavier than CW at the moment of CW (541 vs. 493 kg; and 5.3 vs. 4.3), prepartum (551 vs. 506 kg; and 5.2 vs. 4.4) and 2021-BS (475 vs. 450 kg; and 4.5 vs. 3.7). Plasma urea concentration at 2021-BS was greater (P = 0.01) for PRI than for MUL. A parity-by-time interaction was observed (P ≤ 0.05) for concentrations of IGF-I, NEFA, and BHB. PRI cows had greater (P ≤ 0.05) concentrations of IGF-I at EW and greater (P ≤ 0.05) prepartum concentrations of NEFA and BHB than MUL cows. The proportion of cows with CL at D10 was not affected (P > 0.1) by weaning but was greater (P < 0.05) in MUL than in PRI cows (40.4 vs. 15.7%). The diameter of DF and proportion of BP on D0 were greater (P < 0.05) in EW cows than in CW cows. The pregnancy rate (P/AI, %) at the first TAI was greater (P < 0.05) in EW cows (60% vs. 45%), whereas no difference (P > 0.1) was observed at the second TAI. Cumulative P/AI (first and second TAIs) was greater (P < 0.05) in EW cows (81% vs. 63%). In conclusion, weaning at 150 d in Nelore cattle is a strategy to successfully recover the parous cow's body condition and to improve pregnancy success in the next BS, regardless of the cow's parity order.

The nutritional condition and body energy reserves at parturition are important factors that can affect the reproductive performance of suckled Nelore cows. Also, decreasing the weaning time can benefit the cow's metabolic status. The present study evaluated the effect of two periods of weaning (150 vs. 240 d) on the reproductive performance of the Nelore dam in the subsequent breeding season. The results of the present study indicate that early weaning: 1) improves the body condition, rump fat thickness, and metabolic condition of Nelore cows for the subsequent breeding season; 2) provides better ovarian follicle growth and blood perfusion during the subsequent timed artificial insemination program; 3) enhances the pregnancy rates in the subsequent breeding season.