Blood Metabolite Concentrations Research Articles

Effects of pre- and postpartum dietary fat sources (soybean oil versus linseed oil) on lactation performance and blood metabolites in transition dairy cows

This study investigated the effects of supplementation with two calcium salt fatty acid sources (soybean oil (CaSO) and linseed oil (CaLN)) before and after parturition on lactation performance and blood metabolite profiles in dairy cows. A study was conducted with twenty-four multiparous Holstein cows (parity = 3.12 ± 0.9 and Backfat thickness = 21.77 ± 1.98) that were divided into a 2 × 2 factorial design 21 days before expected calving. The aim was to investigate the interplay between prepartum (CaSO or CaLN, at 2 % of dry matter) and postpartum (at 1.4 % of dry matter) fat supplementation on lactation performance and blood metabolite profiles. Initially, cows were grouped according to the source of prepartum fat (either CaSO or CaLN, with 12 cows in each group). Postpartum, these groups were further subdivided according to whether the fat source was administered continuously (LN-LN, SO-SO) or alternately (LN-SO, SO-LN) over a 28-day period. This resulted in four different treatment groups, each with six cows. The fat supplements contained 84 % fat and 9 % Ca. No statistically significant differences were found in dry matter intake (DMI), colostrum yield or most concentrations of blood metabolites (insulin, cholesterol, glucose, triglycerides, total protein, albumin, β-hydroxybutyric acid (BHB), non-esterified fatty acids (NEFA), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and urea-N). However, cows fed CaSO prepartum had a significantly higher plasma concentration of insulin-like growth factor-1 (IGF-1) than cows fed CaLN. Cows fed CaSO had higher backfat thickness (BFT) from day −21–0 than those fed CaLN (P = 0.05). Notably, cows in the SO-SO group lost the most weight, while cows in the SO-LN group lost the least, especially on days 21 and 28 postpartum (P = 0.05). Switching from soybean oil prepartum to linseed oil postpartum (SO-LN) significantly increased milk production in the first 28 days of lactation compared to other diets. In addition, the fat content in milk was influenced by the type of fat supplementation prepartum, with cows receiving CaSO having a lower milk fat percentage than those receiving CaLN (P < 0.05). The results on blood parameters suggest potential benefits of the SO-LN diet for postpartum cows, as emphasized by stable BHB concentrations and the highest IGF-1 concentrations, especially without the elevated BHB concentrations typically associated with the SO-SO diet. The blood concentrations of total protein, urea-N, triglycerides and NEFA were not affected by the treatments. Also, the dietary change did not adversely affect liver function, as shown by unchanged AST and ALT concentrations. Therefore, the results suggest that a dietary intervention involving the administration of soybean oil prepartum and switching to linseed oil postpartum (SO-LN strategy) has the potential to improve milk yield during the early lactation period.

3-epi-18β-Glycyrrhetinic Acid or Its Glucuronide, the Metabolites of Glycyrrhizinic Acid with Individual Differences, Correlated with Diagnostic Marker for Licorice-Induced Pseudoaldosteronism in Humans.

Licorice is a crude drug that is used in traditional Japanese Kampo medicine and is also used as a sweetener. Occasionally, it causes pseudoaldosteronism (PsA) as a side effect. The major symptoms include hypokalemia, hypertension, edema, and low plasma aldosterone levels. PsA might be caused by the metabolites of glycyrrhizinic acid (GL), a component of licorice. The development of PsA markedly varies among individuals; however, the factors that cause these individual differences remain unknown. In this study, 78 patients who consumed Kampo medicines containing licorice were enrolled, and their laboratory data, including serum potassium levels, plasma aldosterone concentrations (PAC), and the concentrations of GL metabolites in the residual blood and/or urine samples were evaluated. Of the 78 participants, 18β-glycyrrhetinic acid (GA), 3-epi-GA, 3-oxo-GA, 18β-glycyrrhetinyl-30-O-glucuronide (GA30G), and 3-epi-GA30G were detected in the serum samples of 65, 47, 63, 62, and three participants, respectively. Of the 29 urine samples collected, GA30G and 3-epi-GA30G were detected in 27 and 19 samples. 3-epi-GA30G is a newly found GL metabolite. Moreover, 3-epi-GA, 3-oxo-GA, and 3-epi-GA30G were identified in human samples for the first time. High individual differences were found in the appearances of 3-epi-GA in serum and 3-epi-GA30G in urine, and the concentrations of these metabolites were correlated with serum PsA markers. The inhibitory titers of 3-epi-GA, 3-oxo-GA, GA30G, and 3-epi-GA30G on human 11β-hydroxysteroid dehydrogenase type 2 were almost similar. These findings suggest that 3-epi-GA and/or 3-epi-GA30G are associated with individual differences in the development of PsA. SIGNIFICANCE STATEMENT: In this study, we detected 3-epi-18β-glycyrrhetinic acid (3-epi-GA) in human serum for the first time. We also identified 3-epi-18β-glycyrrhetinyl-30-O-glucuronide (3-epi-GA30G) as a novel glycyrrhizinic acid (GL) metabolite in human urine. These GL metabolite levels showed correlations with markers of PsA. Additionally, there are individual differences in whether they appear in the serum/urine. In conclusion, 3-epi-GA/3-epi-GA30G correlates with individual differences in the development of PsA.

T19 - Relationship Between Blood THC and Metabolite Concentrations and Rapidly Collected and Analyzed Breath Samples in Heathy Volunteers After Smoking Marihuana

T19 - Relationship Between Blood THC and Metabolite Concentrations and Rapidly Collected and Analyzed Breath Samples in Heathy Volunteers After Smoking Marihuana

Integrated microbiome and metabolome analysis reveals that new insight into Radix pseudostellariae polysaccharide enhances PRRSV inactivated vaccine.

In this study, we investigated how Radix pseudostellariae polysaccharide (RPP) enhances the immune response of the inactivated porcine reproductive and respiratory syndrome virus (PRRSV) vaccine through interactions with the microbiome and metabolome. We pretreated sows with 10 mg/kg body weight of RPP via drinking water for 7 days prior to intramuscular injection of the PRRSV vaccine. This significantly increased the concentrations of PRRSV GP5 protein antibody, interleukin (IL)-2, IL-4, IL-10, and interferon (IFN)-γ. Oral administration of RPP also significantly improved the abundance of beneficial bacteria in the stool, such as Parabacteroides distasonis, Prevotella_copri, Eubacterium_sp., and Clostridium_sp._CAG:226, and decreased the levels of potentially pathogenic bacteria, such as Paraeggerthella and [Clostridium] innocuum, compared to the vaccine alone. These bacterial changes were confirmed using quantitative real-time polymerase chain reaction (Q-PCR). Moreover, RPP treatment significantly increased the blood concentrations of L-theanine, taurodeoxycholic acid (TDCA), and N-arachidonoyl proline, and decreased the levels of L-glutamine, oclacitinib, lipoxin C4, and leukotriene C5 in sows after immunization (p< 0.05). The concentrations of various blood metabolites were validated using sandwich enzyme-linked immunosorbent assay (ELISA), confirming the accuracy of the metabolomics data. Intriguingly, the integration of microbiome and metabolome analyses highlighted the significance of Prevotella_copri and TDCA. We consequently developed a mouse immunity model using GP5 protein and discovered that oral administration of RPP significantly enhanced the levels of GP5 protein antibodies, IL-2, IL-4, IL-10, and IFN-γ in mouse serum. It also increased the number of CD3+ and CD3+CD4+ cells in the spleen. Additionally, Prevotella_copri was administered into the large intestine via the anus for 7 days prior to the intramuscular injection of the PRRSV GP5 protein. The results demonstrated a significant increase in TDCA and GP5 antibody concentration in the mouse serum, indicating that RPP modulates Prevotella_copri to elevate its metabolite TDCA, thereby enhancing the GP5 antibody level. In conclusion, oral administration of 10 mg/kg RPP optimizes gut flora diversity and blood metabolites, particularly Prevotella_copri and TDCA, thereby improving the immune response to the inactivated PRRSV vaccine.

Effects of lactose content in milk replacer on apparent digestibility, growth, liver mRNA expression, and blood parameters related to metabolism of dairy calves

Even with the same energy supply, differences in energy sources may affect calf growth and metabolism. In this study, we evaluated the effects of feeding 3 different milk replacers (MRs) with different lactose supplies under isoenergetic conditions on calf digestibility, growth, and metabolism-related markers. Fifteen Holstein bull calves were randomly assigned to one of 3 MR-feeding treatments: low-lactose (L:38%), medium-lactose (M:41%), or high-lactose (H:46%). After birth, calves were provided colostrum and treatment MRs were fed from 1 d of age and gradually increased to a maximum feeding rate at 20 d of age (L:1.16 kg/d, M:1.21 kg/d, H:1.26 kg/d DM) without feeding solid feeds during the experimental period. Blood samples were temporarily collected weekly to assess blood concentrations of metabolites and hormones. From 30 to 36 d of age, the calves were euthanized and liver samples were collected to determine growth-related mRNA expression. L calves showed a greater body length than H calves and the highest GHR mRNA expression. Plasma concentrations of total cholesterol, urea nitrogen, total protein, albumin, insulin, and insulin-growth factor-1 were not different, but plasma concentrations of triglycerides were higher in order H, M, and L. These results showed that the difference in lactose content in the MR affected calf metabolism, and the L-MR was suggested to be more likely to enhance growth into the peripheral tissues.

Localized mammary gland changes in milk composition and venous blood metabolite concentrations result from sterile subclinical mastitis

Subclinical mastitis reduces milk yield and elicits undesirable changes in milk composition, but the mechanisms resulting in reduced milk production in affected mammary glands are incompletely understood. This study investigated the effects of sterile inflammation on mammary gland metabolism by assessing changes in milk and venous blood composition. Mid-lactation primiparous Holstein cows (n = 4) had udder halves randomly allocated to treatments; quarters of 1 udder half were infused with 2 billion cfu of formalin fixed Staphylococcus aureus (FX-STAPH) and quarters of the opposite udder half infused with saline (SAL). Blood samples were collected from the right and left subcutaneous abdominal veins in 2.6 h intervals until 40 h post challenge and analyzed for blood gas and metabolite concentrations. Milk from FX-STAPH udder halves had significantly increased SCS by first milking at 8 h post-challenge. By 16 h post-challenge, FX-STAPH udder halves had increased concentrations of protein and lactate and lower lactose concentrations than SAL udder halves. Milk fat concentrations, milk yields, energy corrected milk yields, and the ferric reducing antioxidant power of milk were not significantly different between SAL and FX-STAPH udder halves. Venous blood of FX-STAPH halves had marginally greater concentrations of saturated O2, partial pressures of O2, and glucose concentrations than SAL halves. Conversely, total and partial pressures of CO2 did not differ between udder half treatments suggesting a shift in local metabolite utilization in FX-STAPH udder halves. These results indicate that changes in milk composition resulting from mastitis are accompanied by changes in some key blood metabolite concentrations. The shift in venous blood metabolite concentrations, along with the marked increase in milk lactate, suggests that local mammary tissue and/or recruited and immune cells alters metabolite usage in mammary tissues. Future studies are needed to quantify the uptake of key milk precursors during mastitis.

Sex and age disparities in multi-metal mixture exposure and cognitive impairment in urban elderly individuals: The mediation effect and biological function of metabolites

Studies on the relationships between metal mixtures exposure and cognitive impairment in elderly individuals are limited, particularly the mechanism with metabolite. Few studies are available on the potential sex and age specific associations between metal exposure, metabolites and cognitive impairment. We examined plasma metal and blood metabolite concentrations among 1068 urban elderly participants. Statistical analysis included a battery of variable selection approaches, logistic regression for metal/metabolite associations, and Bayesian kernel machine regression (BKMR) to identify mixed effects of metals/metabolites on cognitive impairment risk. Our results showed that As was positively associated with cognitive impairment in the female (OR 95 % CI = 2.21 (1.36, 3.57)) and 60- to 70-year-old (OR 95 % CI = 2.60 (1.54, 4.41)) groups, Cr was positively associated with cognitive impairment in the male (OR 95 % CI = 2.15 (1.27, 3.63)) and 60- to 70-year-old (OR 95 % CI = 2.10 (1.24, 3.57)) groups, and Zn was negatively associated with cognitive impairment, especially in the female (OR 95 % CI = 0.46 (0.25, 0.84)), 60- to 70-year-old (OR 95 % CI =0.24 (0.12, 0.45)) and ≥ 80-year-old (OR 95 % CI = 0.19 (0.04, 0.86)) groups. Positive associations were observed between combined metals (Cr, Cu and As) and cognitive impairment, but Zn alleviated this tendency, especially in elderly individuals aged ≥80 years. Negative associations were observed between metabolites and cognitive impairment, especially in male, female and 60–70 years old groups. The mediation effects of metabolites on the association between metal exposure and cognitive impairment were observed, and the percentages of these effects were 15.60 % (Glu-Cr), 23.00 % (C5:1-Cu) and 16.36 % (Glu-Zn). Cr, Cu, and Zn could increase cognitive impairment risk through the “Malate−Aspartate Shuttle”, “Glucose−Alanine Cycle”, etc., pathways. Overall, we hypothesize that metabolites have mediation effects on the relationship between multi-metal exposure and cognitive impairment and that there are sex and age differences.

Complexity of Translating Analytics to Recent Cannabis Use and Impairment.

While current analytical methodologies can readily identify cannabis use, definitively establishing recent use within the impairment window has proven to be far more complex, requiring a new approach. Recent studies have shown no direct relationship between impairment and Δ9-tetra-hydrocannabinol (Δ9-THC) concentrations in blood or saliva, making legal "per se" Δ9-THC limits scientifically unjustified. Current methods that focus on Δ9-THC and/or metabolite concentrations in blood, saliva, urine, or exhaled breath can lead to false-positive results for recent use due to the persistence of Δ9-THC well outside of the typical 3-4 h window of potential impairment following cannabis inhalation. There is also the issue of impairment due to other intoxicating substances-just because a subject exhibits signs of impairment and cannabis use is detected does not rule out the involvement of other drugs. Compounding the matter is the increasing popularity of hemp-derived cannabidiol (CBD) products following passage of the 2018 Farm Bill, which legalized industrial hemp in the United States. Many of these products contain varying levels of Δ9-THC, which can lead to false-positive tests for cannabis use. Furthermore, hemp-derived CBD is used to synthesize Δ8-THC, which possesses psychoactive properties similar to Δ9-THC and is surrounded by legal controversy. For accuracy, analytical methods must be able to distinguish the various THC isomers, which have identical masses and exhibit immunological cross-reactivity. A new testing approach has been developed based on exhaled breath and blood sampling that incorporates kinetic changes and the presence of key cannabinoids to detect recent cannabis use within the impairment window without the false-positive results seen with other methods. The complexity of determining recent cannabis use that may lead to impairment demands such a comprehensive method so that irresponsible users can be accurately detected without falsely accusing responsible users who may unjustly suffer harsh, life-changing consequences.

A 6-month exercise intervention clinical trial in women: effects of physical activity on multi-omics biomarkers and health during the first wave of COVID-19 in Korea

BackgroundCoronavirus disease 2019 (COVID-19) was first reported in December 2019 and the first case in Korea was confirmed on January 20, 2020. Due to the absence of therapeutic agents and vaccines, the Korean government implemented social distancing on February 29, 2020. This study aimed to examine the effect of physical activity (PA) on health through changes in multi-omics biomarkers with a 6-month of exercise intervention during the first wave of COVID-19 in Korea.MethodsTwenty-seven healthy middle-aged women were recruited and 14 subjects completed the exercise intervention. The mean age (± SD) was 46.3 (± 5.33) and the mean BMI (± SD) was 24.9 (± 3.88). A total of three blood and stool samples were collected at enrollment, after period 1, and after period 2 (3-month intervals). The amount of PA was measured with an accelerometer and by questionnaire. Clinical variables were used, including blood pressure, grip strength, flexibility, and blood glucose levels and lipid markers obtained from laboratory tests. The concentration of blood metabolites was measured by targeted metabolomics. Fecal microbiome data were obtained by 16 S rRNA gene amplicon sequencing.ResultsDuring the second half period (period 2), Coronavirus disease 2019 occurred and spread out in Korea, and PA decreased compared with the first half period (period 1) (185.9 ± 168.73 min/week to 102.5 ± 82.30 min/week; p = 0.0101). Blood pressure, hemoglobin A1c (HbA1c), and low-density lipoprotein cholesterol (LDL-C) decreased in period 1 (p < 0.05) and tended to increase again during period 2 (p < 0.05). Forty metabolites were changed significantly during period 1 (FDR p < 0.05), and we found that 6 of them were correlated with changes in blood pressure, HbA1c, and LDL-C via network analysis.ConclusionsOur results may suggest that exercise improves health through changes in biomarkers at multi-omics levels. However, reduced PA due to COVID-19 can adversely affect health, emphasizing the necessity for sustained exercise and support for home-based fitness to maintain health.Trial RegistrationThe trial is retrospectively registered on ClinicalTrials.gov (NCT05927675; June 30, 2023).

Fetal programming effect of rumen-protected methionine on primiparous Angus × Simmental offspring's performance and skeletal muscle gene expression.

Primiparous Angus × Simmental dams (n = 22) with an average body weight (BW) of 449 ± 32kg of BW were divided based on two nutritional treatments: control (CTRL) and rumen-protected methionine (RPM). The control group received bermudagrass hay, corn gluten, and soybean hulls pellets supplementation (base diet); whereas the RPM group received the base diet in addition to 0.07% of DM of RPM at a fixed rate during the last trimester of gestation and the first ~80d of lactation, in which calves (n = 17) were early weaned. Only male calves were included in this study. After weaning, calves born to RPM dams also received RPM from weaning (day 1) to day 100. Blood sampling and skeletal muscle biopsies for subsequent quantitative polymerase chain reaction (PCR) analysis were conducted on days 1, 25, 50, and 100 on calves. Quantitative PCR data were analyzed using GLIMMIX, and blood metabolites concentrations, BW, and body condition score (BCS) were analyzed using the MIXED procedure of SAS. There was no difference in maternal BW and BCS between treatments. Glucose and blood metabolites that served as biomarkers for liver health (e.g., aspartate transaminase, albumin, alkaline phosphatase, and alanine transaminase) were in the normal levels for all calves (P > 0.40). Calves in the RPM group had a greater expression of adipogenic genes (e.g., PPARG, LPL, and CEBPD) at day 100 compared with CTRL (P < 0.01). In addition, DNA methylation (DNMT1) and oxidative stress-related genes (SOD2 and NOS3) in the RPM group were upregulated at day 100 compared with CTRL (P < 0.01). These results may suggest that calves born to primiparous dams exposed to RPM supplementation are more prone to develop greater adipose tissue than CTRL calves. Furthermore, RPM supplementation may improve methylation processes, as shown by the upregulation of DNMT1. The results shown in our study aim at expanding the knowledge on fetal programming and early-life growth and development of beef cattle under supplementation with RPM.

Effects of starch content of calf starter on rumen properties and blood concentrations of metabolites and hormones in dairy calves under a high plane of milk feeding.

The objective of this study was to investigate the effects of calf starters with different starch content on rumen and blood properties in calves fed under a high plane of nutrition program. Twenty-seven Holstein calves (14 female, 13 male) were assigned to one of three starter treatment groups in a randomized block design: high-starch (41.8%) (n= 9), H; medium-starch (31.9%) (n= 9), M; low-starch (22.0%) (n= 9), L. Milk replacer on powder basis was fed up to 1.2kg/day as fed, gradually reduced from 6weeks of age; calves were weaned at 8weeks of age. Each starter (up to 3.5kg/day as fed) and chopped hay were provided ad libitum from 5days of age. Blood was collected from 4 to 13 weeks of age. Rumen fluid was collected at 6, 8, 10, and 13 weeks of age. Serum urea nitrogen concentration after weaning was the lowest in H. Plasma IGF-1 concentrations were higher in H than in L. Ruminal pH was not different, but the molar proportion of ruminal propionate was higher in H than in L throughout the study period. In summary, a high-starch starter may increase propionate production and microbial protein synthesis in the rumen, inducing higher plasma IGF-1 concentrations.

Lipid metabolites index habitat quality for Canvasbacks on stopover areas during spring migration

Abstract Nutrients acquired by ducks on spring migratory stopover areas influence survival and subsequent reproduction. Accordingly, wetland loss and degradation on stopover areas can lead to reduced refueling efficiency and have demographic consequences. Lipid metabolite concentrations in blood provide a useful index of daily mass change in wild birds and can be used to make inferences about quality of stopover areas for refueling. We experimentally validated a model that uses lipid metabolites to predict daily mass change, and then we used those predictions to make inferences about foraging habitat quality for Canvasbacks (Aythya valisineria) at important stopover sites of the upper Mississippi and Illinois Rivers, USA. We measured plasma lipid metabolites and daily mass change of 60 wild Canvasbacks held in short-term captivity and subjected to feeding and fasting treatments. Respectively, triglyceride and β-hydroxybutyrate concentrations were positively and negatively related to mass change (R2 = 0.58). On average, Canvasbacks collected experimentally across our study area had positive index values indicating sufficient forage resources to allow energy acquisition. However, predicted daily mass increases were greater at more northerly pools of the Mississippi River (Pools 7–8 and 13) compared to more southerly locations (Pool 19 of the Mississippi River and the Illinois River Valley), which was likely due, in part, to more abundant submerged aquatic vegetation at more northerly pools. Our results affirm that lipid metabolites are useful predictors of daily mass change that in turn can provide inferences about habitat quality. Lower daily mass increases of Canvasbacks at Pool 19 are concerning because that area is considered a critically important spring stopover area for migratory diving ducks. Considering the challenges of managing large rivers for multiple uses, targeting restoration of wetlands isolated or isolatable from river systems could provide stopover areas with necessary forage for optimal mass gain.

62 Exploration of Sex Differences in Cannabis Use Patterns, Driving Performance, and Subjective Intoxication Effects

Objective:Although some animal research suggests possible sex differences in response to THC exposure (e.g., Cooper &amp; Craft, 2018), there are limited human studies. One study found that among individuals rarely using cannabis, when given similar amounts of oral and vaporized THC females report greater subjective intoxication compared to males (Sholler et al., 2020). However, in a study of daily users, females reported indistinguishable levels of intoxication compared to males after smoking similar amounts (Cooper &amp; Haney, 2014), while males and females using 1–4x/week showed similar levels of intoxication, despite females having lower blood THC and metabolite concentrations (Matheson et al., 2020). It is important to elucidate sex differences in biological indicators of cannabis intoxication given potential driving/workplace implications as states increasingly legalize use. The current study examined if when closely matching males and females on cannabis use variables there are predictable sex differences in residual whole blood THC and metabolite concentrations, and THC/metabolites, subjective appraisals of intoxication, and driving performance following acute cannabis consumption.Participants and Methods:The current study was part of a randomized clinical trial (Marcotte et al., 2022). Participants smoked ad libitum THC cigarettes and then completed driving simulations, blood draws, and subjective measures of intoxication. The main outcomes were the change in Composite Drive Score (CDS; global measure of driving performance) from baseline, whole blood THC, 11-OH-THC, and THC-COOH levels (ng/mL), and subjective ratings of how “high” participants felt (0 = not at all, 100 = extremely). For this analysis of participants receiving active THC, males were matched to females on 1) estimated THC exposure (g) in the last 6 months (24M, 24F) or 2) whole blood THC concentrations immediately post-smoking (23M, 23F).Results:When matched on THC exposure in the past 6 months (overall mean of 46 grams; p = .99), there were no sex differences in any cannabinoid/metabolite concentrations at baseline (all p &gt; .83) or after cannabis administration (all p &gt; .72). Nor were there differences in the change in CDS from pre-to-post-smoking (p = .26) or subjective “highness” ratings (p = .53). When matched on whole blood THC concentrations immediately after smoking (mean of 34 ng/mL for both sexes, p = .99), no differences were found in CDS change from pre-to-post smoking (p = .81), THC metabolite concentrations (all p &gt; .25), or subjective “highness” ratings (p = .56). For both analyses, males and females did not differ in BMI (both p &gt; .7).Conclusions:When male/female cannabis users are well-matched on use history, we find no significant differences in cannabinoid concentrations following a mean of 5 days of abstinence, suggesting that there are no clear biological differences in carryover residual effects. We also find no significant sex differences following ad libitum smoking in driving performance, subjective ratings of “highness,” nor whole blood THC and metabolite concentrations, indicating that there are no biological differences in acute response to THC. This improves upon previous research by closely matching participants over a wider range of use intensity variables, although the small sample size precludes definitive conclusions.

Efficacy of concentrates containing tropical weed Chromolaena odorata, methionine hydroxy analog and palm oils in fattening male Bali cattle: A physiological study

Chromolaena odorata is a potential feed source but is low in methionine, which might affect the rumen function. Therefore providing efficient nutrient/s might improve rumen function. The study aimed to assess the efficacy of a concentrate containing Chromolaena odorata meal, hydroxy methionine analog (HMA), and palm oil on blood metabolites of fattened cattle. Sixteen Bali cattle (Bos sondaicus) with an average body weight of 130.5kg ± 32.5 were allotted into four dietary treatments (and four replicates) using a Completely Randomized Block Design with 4 cattle in each Group. The treatments were concentrates with no addition of palm oil and/or HMA as the control diet (Group I) , added with 3 g HMA (CMA) (Group II), added with 0.5% palm oil (Group III) and (CPO) added with a combination of 3 g HMA and 0.5% palm oil (CMO) Group IV). The concentrate was offered to the animals at a rate of 2% liveweight, whilst rice straws were provided ad libitum as the source of fiber. The concentrate contained 18% crude protein and 12 MJ ME/kg DM to target a live weight gain of at least 0.6 kg/day. Blood metabolites measured were total cholesterol levels, plasma glucose, plasma proteins, and plasma urea. Collected data were subjected to analysis of variance with the significance level set at an alpha value of ≤ 0.05. The results showed that providing concentrate-containing. C. odorata with or without HMA and/or palm oil (Group IV) only significantly affected blood plasma proteins, whereas other blood metabolites were unaffected. It might be concluded that there is no benefit of adding palm oil or methionine analog to chromolaena-based concentrate for fattened cattle since it will not affect the concentration of blood metabolites.

Effects of temperature-humidity index on blood metabolites of German dairy cows and their female calves

Heat stress (HS) impairs productivity, health, and welfare in dairy cows, and additionally causes metabolic changes. Hence, specific metabolites could be used as HS biomarkers. Consequently, the aim of the present study was to compare blood metabolite concentrations of German Holstein dairy cows and of their female calves suffering from high temperature-humidity index (THI) during late gestation (cows) or during their first week of life (calves) or not. According to the mean daily THI (mTHI) at the day before blood sampling, animals were classified into 2 groups: high mTHI ≥60 (hmTHI) and low mTHI <60 (lmTHI). To perform a standard cross-sectional 2-group study, cow groups (n = 48) and calf groups (n = 47) were compared separately. Differences in metabolite concentrations between hmTHI and lmTHI animals were inferred based on a targeted metabolomics approach. In the first step, processed metabolomics data were evaluated by multivariate data analysis techniques, and were visualized using the web-based platform MetaboAnalyst V5.0. The most important metabolites with pronounced differences between groups were further analyzed in a second step using linear mixed models. We identified 9 thermally sensitive metabolites for the cows [dodecanedioic acid; 3-indolepropionic acid; sarcosine; triglycerides (14:0_34:0), (16:0_38:7), (18:0_32:1), and (18:0_36:2); phosphatidylcholine aa C38:1; and lysophosphatidylcholine a C20:3] and for the calves [phosphatidylcholines aa C38:1, ae C38:3, ae C36:0, and ae C36:2; cholesteryl esters (17:1) and (20:3); sphingomyelins C18:0 and C18:1; and p-cresol sulfate], most of them related to lipid metabolism. Apart from 2 metabolites (3-indolepropionic acid and sarcosine) in cows, the metabolite plasma concentrations were lower in hmTHI than in lmTHI groups. In our heat-stressed dry cows, results indicate an altered lipid metabolism compared with lactating heat-stressed cows, due to the missing antilipolytic effect of HS. The results also indicate alterations in lipid metabolism of calves due to high mTHI in the first week of life. From a cross-generation perspective, high mTHI directly before calving seems to reduce colostrum quality, with detrimental effects on metabolite concentrations in offspring.

Pre-calving energy density and rumen protected lysine impacted blood metabolites and biomarkers of liver functions in dairy cows during the transition period.

Dairy cows usually face negative energy balance and disorders of normal organ function due to a mismatch between energy intake and energy demand. Negative energy balance directly affects liver function and blood metabolites because the liver is used as source of energy supply and a center of metabolic activity. This study was aimed to determine the effect of pre-calving energy density and rumen-protected lysine on blood metabolites and biomarkers of liver functions in the dairy cows during the transition period. Forty 3rd lactation Holstein cows going to enter their 4th lactation were randomly allocated to one of the four dietary treatments (high energy with rumen-protected lysine (HERPL) = 1.53NEL plus 40g Lys, high energy without lysine (HECK) = 1.53NEL, low energy with rumen-protected lysine (LERPL) = 1.37NEL plus 40g Lys, and low energy without lysine (LECK) = 1.37NEL arranged in a 2 × 2 factorial design. Blood samples were collected during the transition period, and concentrations of blood metabolites and biomarkers of liver function were measured. Interaction between pre-calving high-energy diet and rumen-protected lysine tended to increase plasma albumin, numerically increased glucose, decreased triglyceride, total bilirubin, and aspartate aminotransferase concentrations. The result revealed that pre-calving high-energy density increased insulin, albumin and decreased blood urea nitrogen and total bilirubin concentrations and substantial favor liver functions during the transition period.

Identification of blood metabolites linked to the risk of intervertebral disc diseases: a comprehensive Mendelian randomization study.

Intervertebral disc degeneration (IVDD) has affected millions of people worldwide and dramatically affects human beings' quality of life. Observational studies hypothesize that metabolites play key roles as markers and effectors of IVDD, but their causality has not yet been illustrated. We conducted comprehensive Mendelian randomization (MR) to determine the causal relationship between 249 plasma metabolites and IVDD. Inverse-variance weighting was used as the primary estimate, whereas MR-Egger and weighed median were used to detect robustness. A series of sensitivity analyses including Cochran Q test, leave one out, and MR-Egger intercept analysis were also conducted. In total, we found 13 blood metabolites significantly associated with IVDD, including phospholipids in very large high-density lipoprotein (HDL), free cholesterol to total lipids ratio in very large HDL, average diameter for HDL particles, cholesteryl esters to total lipids ratio in large HDL, free cholesterol to total lipids ratio in medium HDL, creatinine, free cholesterol to total lipids ratio in large HDL, phospholipids to total lipids ratio in very large HDL, cholesterol to total lipids ratio in very large HDL, cholesteryl esters to total lipids ratio in large HDL, phospholipids in large HDL, total lipids in very large HDL, and total lipids in large HDL. No pleiotropy was detected. Heterogeneity existed in several estimates and random-effect inverse-variance weighting was applied. Our study highlighted the causal association of blood metabolites with the risk of IVDD. Our results provide new insights into possible treatment protocols controlling the concentration of specific blood metabolites in IVDD patients. Key messages What is already known on this topic Low back pain is the most common symptom for patients with intervertebral disc degeneration (IVDD) and influences the quality of life of large populations. Observational studies have indicated the association between metabolites and IVDD. However, causality has not been determined yet. What this study adds We conducted a comprehensive Mendelian randomization study to reveal the causal effect from 249 blood metabolites on low back pain. A total of 13 metabolites were found to causally affect the risk of IVDD, among which 11 were negatively associated and 2 were positively asscociated. How this study might affect research, practice, or policy These 13 significant metabolites could serve as biomarkers for IVDD and our results provide new insights into possible treatment protocols for IVDD patients.

Higher Plasma Creatinine Is Associated with an Increased Risk of Death in Patients with Non-Metastatic Rectal but Not Colon Cancer: Results from an International Cohort Consortium.

Colorectal cancer (CRC) is increasingly recognized as a heterogeneous disease. No studies have prospectively examined associations of blood metabolite concentrations with all-cause mortality in patients with colon and rectal cancer separately. Targeted metabolomics (Biocrates AbsoluteIDQ p180) and pathway analyses (MetaboAnalyst 4.0) were performed on pre-surgery collected plasma from 674 patients with non-metastasized (stage I-III) colon (n = 394) or rectal cancer (n = 283). Metabolomics data and covariate information were received from the international cohort consortium MetaboCCC. Cox proportional hazards models were computed to investigate associations of 148 metabolite levels with all-cause mortality adjusted for age, sex, tumor stage, tumor site (whenever applicable), and cohort; the false discovery rate (FDR) was used to account for multiple testing. A total of 93 patients (14%) were deceased after an average follow-up time of 4.4 years (60 patients with colon cancer and 33 patients with rectal cancer). After FDR adjustment, higher plasma creatinine was associated with a 39% increase in all-cause mortality in patients with rectal cancer. HR: 1.39, 95% CI 1.23-1.72, pFDR = 0.03; but not colon cancer: pFDR = 0.96. Creatinine is a breakdown product of creatine phosphate in muscle and may reflect changes in skeletal muscle mass. The starch and sucrose metabolisms were associated with increased all-cause mortality in colon cancer but not in rectal cancer. Genes in the starch and sucrose metabolism pathways were previously linked to worse clinical outcomes in CRC. In summary, our findings support the hypothesis that colon and rectal cancer have different etiological and clinical outcomes that need to be considered for targeted treatments.

Physiological roles and regulation of hepatic angiopoietin-like protein 3 in Japanese Black cattle (Bos taurus) during the fattening period.

Angiopoietin-like protein 3 (ANGPTL3) is expressed predominantly in the liver and plays a major role in regulating the circulating triglyceride and lipoprotein fraction concentrations by inhibiting lipoprotein lipase (LPL) activity. Given these physiological roles, ANGPTL3 may play an important role in metabolic changes related to fat accumulation during the fattening period in Japanese Black. This study aimed to reveal the physiological roles of hepatic ANGPTL3 in Japanese Black steers (Bos taurus) during the fattening period and investigate the regulatory effects of hepatic ANGPTL3. To investigate the gene expression and protein localization of ANGPTL3, 18 tissue samples were collected from tree male Holstein bull calves aged 7 wk. Biopsied liver tissues and blood samples were collected from 21 Japanese Black steers during the early (T1; 13 mo of age), middle (T2; 20 mo), and late fattening phases (T3; 28 mo). Relative mRNA expression, blood metabolite concentrations, hormone concentrations, growth, and carcass traits were analyzed. To identify the regulatory factors of hepatic ANGPTL3, primary bovine hepatocytes collected by two Holstein calves aged 7 wk were incubated with insulin, palmitate, oleate, propionate, acetate, or beta-hydroxybutyric acid (BHBA). The ANGPTL3 gene was most highly expressed in the liver, with minor expression in the renal cortex, lungs, reticulum, and jejunum in Holstein bull calves. In Japanese Black steers, relative ANGPTL3 mRNA expressions were less as fattening progressed, and blood triglyceride, total cholesterol, and nonesterified fatty acid (NEFA) concentrations increased. Relative ANGPTL8 and Liver X receptor alpha (LXRα) mRNA expressions decreased in late and middle fattening phases, respectively. Furthermore, relative ANGTPL3 mRNA expression was positively correlated with ANGPTL8 (r = 0.650; P < 0.01) and ANGPTL4 (r = 0.540; P < 0.05) in T3 and T1, respectively, and LXRα showed no correlation with ANGPTL3. Relative ANGTPL3 mRNA expression was negatively correlated with total cholesterol (r = -0.434; P < 0.05) and triglyceride (r = -0.645; P < 0.01) concentrations in T3 and T1, respectively; There was no significant correlation between ANGTPL3 and carcass traits. Relative ANGTPL3 mRNA expression in cultured bovine hepatocytes was downregulated in oleate treatment. Together, these findings suggest that ANGPTL3 downregulation in late fattening phases is associated with the changes in lipid metabolism.

Pharmacogenetics of Lethal Opioid Overdose: Review of Current Evidence and Preliminary Results from a Pilot Study.

There has been a worldwide substantial increase in accidental opioid-overdose deaths. The aim of this review, along with preliminary results from our pilot study, is to highlight the use of pharmacogenetics as a tool to predict causes of accidental opioid-overdose death. For this review, a systematic literature search of PubMed® between the time period of January 2000 to March 2023 was carried out. We included study cohorts, case-controls, or case reports that investigated the frequency of genetic variants in opioid-related post-mortem samples and the association between these variants and opioid plasma concentrations. A total of 18 studies were included in our systematic review. The systematic review provides evidence of the use of CYP2D6, and to a lower extent, CYP2B6 and CYP3A4/5 genotyping in identifying unexpectedly high or low opioid and metabolite blood concentrations from post-mortem samples. Our own pilot study provides support for an enrichment of the CYP2B6*4-allele in our methadone-overdose sample (n = 41) compared to the anticipated frequency in the general population. The results from our systematic review and the pilot study highlight the potential of pharmacogenetics in determining vulnerability to overdose of opioids.