Liver Function Research Articles

Secondary bile acids in portal blood contribute to liver regeneration in a rat model of partial hepatectomy.

Gut metabolites via the portal vein affect several liver functions, including regeneration. Here, we investigated gut microbiota-derived metabolites in portal and peripheral serum during liver regeneration. We developed rat models of 70% partial hepatectomy (PHx) with and without prior gut microbiota modulation by three-week antibiotic (Abx) treatment. Sham without Abx were used as controls and compared to sham with Abx. Liver regeneration at day 2 following PHx was assessed by expression of proliferating cell nuclear antigen (PCNA) protein in liver tissues and cyclin genes in primary hepatocytes. High pressure liquid chromatography-mass spectrometry (HPLC-MS) based portal and peripheral venous serum metabolomics was performed to identify differentially altered metabolites (DAMs). Compared to controls, rat livers at day 2 post-PHx showed significant upregulation in the average number of PCNA-positive cells, which positively correlated with the expression of cell cycle genes in hepatocytes. In Abx-treated PHx, we observed reduced PCNA-positivity and downregulation in gene expression of various cyclins in hepatocytes compared to PHx. We identified 224 DAMs between controls vs PHx and 189 DAMs between Abx-treated PHx vs PHx in portal serum. Many common DAMs showed opposite expression trends in PHx vs controls and then Abx+PHx vs PHx in portal serum, such as sphingosine-1-phosphate and deoxycholic acid. In vitro studies with deoxycholic acid demonstrated that it enhanced the viability and proliferation of primary hepatocytes and hepatocyte organoids. The study underscores the critical role of deoxycholic acid in portal blood in enhancing hepatocyte proliferation and subsequently, liver regeneration.

Age, Gender, and BMI Modulate the Hepatotoxic Effects of Brominated Flame Retardant Exposure in US Adolescents and Adults: A Comprehensive Analysis of Liver Injury Biomarkers

Brominated flame retardants (BFRs), commonly found in consumer products, have been identified as potential hazards to liver function. While the individual effects of specific BFRs are somewhat understood, there is limited evidence on how mixtures of these chemicals, especially when influenced by demographic factors, interact to affect liver function. This study utilized data from 10,828 participants aged 12 and above from the National Health and Nutrition Examination Survey (2005–2016) to investigate the associations between BFRs (both individually and in combinations) and biomarkers of liver injury. The study focused on how age, gender, and body mass index (BMI) modify modulate these effects. Multivariate linear regression, restricted cubic spline function, weighted quantile sum (WQS) regression, and quantile g-computation (qgcomp) models were used to analyze the linear, non-linear, and joint associations between BFR levels and liver function parameters. We found positive associations between the mixed BFRs index and AST, ALT, GGT, ALP, and TBIL levels and a negative association with ALB levels. PBDE28, PBDE47, and PBB153 consistently contributed to the top weight in both the WQS and qgcomp models. Most critically, the study demonstrated that the relationship between co-exposure to BFRs and liver function parameters was modified by age, gender, and BMI. Therefore, our study highlights the importance of considering demographic diversity in assessing the risk of BFR-induced liver damage and supports the implementation of tailored preventive and intervention strategies.

What Not to Overlook in the Management of Patients with Type 2 Diabetes Mellitus: The Nephrological and Hepatological Perspectives

Diabetes mellitus (DM) significantly impacts renal and hepatic function, necessitating comprehensive understanding and management strategies. Renal involvement, namely diabetic kidney disease (DKD), presents a global challenge, with increasing prevalence paralleling DM rates. Lifestyle modifications and pharmacotherapy targeting hypertension and glycemic control have pivotal roles in DKD management. Concurrently, hepatic involvement in DM, characterized by metabolic dysfunction-associated steatotic liver disease (MASLD), presents a bidirectional relationship. DM exacerbates MASLD progression, while MASLD predisposes to DM development and worsens glycemic control. Screening for MASLD in DM patients is of high importance, utilizing non-invasive methods like ultrasound and fibrosis scores. Lifestyle modifications, such as weight loss and a Mediterranean diet, mitigate MASLD progression. Promising pharmacotherapies, like SGLT2 inhibitors and GLP-1 agonists, demonstrate efficacy in both DM and MASLD management. Special populations, such as diabetic individuals undergoing hemodialysis or kidney transplant recipients, demand special care due to unique clinical features. Similarly, DM exacerbates complications in MASLD patients, elevating the risks of hepatic decompensation and hepatocellular carcinoma. Recognizing the interconnectedness of DM, renal, and hepatic diseases underscores the need for multidisciplinary approaches for optimal patient outcomes. The present review aims to present the main characteristics and crucial points not to be overlooked regarding the renal and hepatic involvement in DM patients focusing on the inter-relationships between the renal and the hepatic involvements.

Superior cuproptotic efficacy of diethyldithiocarbamate-Cu4O3 nanoparticles over diethyldithiocarbamate-Cu2O nanoparticles in metastatic hepatocellular carcinoma

Metastatic hepatocellular carcinoma (HC) is a serious health concern. The stemness of cancer stem cells (CSCs) is a key driver for HC tumorigenesis, apoptotic resistance, and metastasis, and functional mitochondria are critical for its maintenance. Cuproptosis is Cu-dependent non-apoptotic pathway (mitochondrial dysfunction) via inactivating mitochondrial enzymes (pyruvate dehydrogenase “PDH” and succinate dehydrogenase “SDH”). To effectively treat metastatic HC, it is necessary to induce selective cuproptosis (for halting cancer stemness genes) with selective oxidative imbalance (for increasing cell susceptibility to cuproptosis and inducing non-CSCs death). Herein, two types of Cu oxide nanoparticles (Cu4O3 “C(I + II)” NPs and Cu2O “C(I)” NPs) were used in combination with diethyldithiocarbamate (DD, an aldehyde dehydrogenase “ALDH” inhibitor) for comparative anti-HC investigation. DC(I + II) NPs exhibited higher cytotoxicity, mitochondrial membrane potential, and anti-migration impact than DC(I) NPs in the treated human HC cells (HepG2 and/or Huh7). Moreover, DC(I + II) NPs were more effective than DC(I) NPs in the treatment of HC mouse groups. This was mediated via higher selective accumulation of DC(I + II) NPs in only tumor tissues and oxidant activity, causing stronger selective inhibition of mitochondrial enzymes (PDH, SDH, and ALDH2) than DC(I)NPs. This effect resulted in more suppression of tumor and metastasis markers as well as stemness gene expressions in DC(I + II) NPs-treated HC mice. In addition, both nanocomplexes normalized liver function and hematological parameters. The computational analysis found that DC(I + II) showed higher binding affinity to most of the tested enzymes. Accordingly, DC(I + II) NPs represent a highly effective therapeutic formulation compared to DC(I) NPs for metastatic HC.

Quantitative and qualitative evaluation of high-quality hepatobiliary phase imaging with shortened timing and utility in patients with compromised liver function.

To compare high flip angle (FA) hepatobiliary-phase (hHBP) imaging with variable time intervals to conventional HBP (cHBP) to assess the impact of increased FA on image quality in shortened HBP imaging. Data from 218 patients, divided into normal liver group (n = 184) and decompensated liver group (n = 34), who underwent liver magnetic resonance imaging (MRI) including 10-min, 15-min, 20-min hHBP, and cHBP were analyzed. Signal-to-noise ratio (SNR), contrast-ratio (CR), contrast-to-noise ratio (CNR), signal intensity ratios (SIRs), and relative enhancement (RE) of the liver were calculated for quantitative analysis. Sharpness, noise, and artifacts of the image, contrast media visibility, overall image quality, and lesion conspicuity were evaluated by two abdominal radiologists. Quantitative analysis showed that SNR, RE, SIR for liver/muscle, liver/spleen, and CR of all hHBP images demonstrated a significantly higher value compared to cHBP images in the normal liver group (p < 0.001). These values were also superior in the normal liver group compared to the decompensated liver group (p < 0.01). In qualitative analysis, both normal and decompensated liver groups exhibited significantly superior image sharpness in all hHBP images compared to cHBP images and the overall image quality of the 15-min and 20-min hHBP did not show significant difference compared to cHBP. All values tended to be better in the normal liver group than the decompensated liver group with statistical significance except for lesion conspicuity (p < 0.01). High-FA HBP has proven to be a valuable image acquisition method, potentially shortening liver MR imaging time while maintaining acceptable image quality.

ALT in Preeclampsia

Background: Preeclampsia is the most frequent cause of abnormal liver function test in pregnancy. Women with preeclampsia and raised serum alanine aminotransferase (ALT) have chance of greater proteinuria and more maternal complications than those with normal liver function. Objective: The present study was designed to assess the association of serum ALT with preeclampsia. Materials and method: A case control study was conducted in the Department of Biochemistry, Dhaka Medical College,Dhaka, Bangladesh, from July 2010 to June 2011. From the pregnant women in third trimester of pregnancy attending in Obstetrics and Gynecology Department of Dhaka Medical College Hospital, 50 diagnosed cases of preeclampsia were selected purposively as cases and 50 normal healthy pregnant women as controls. Serum ALT concentration was measured in all the study subjects. Results: The mean serum ALT concentration in cases and controls were 57.92±20.99 U/L and 15.46±2.66 U/L respectively. The level was significantly higher in cases than that of controls (p=0.001). Conclusion: The study revealed that increased serum ALT concentration is associated with preeclampsia. Delta Med Col J. Jan 2021;9(2): 65-68

The role of NAD-dependent deacetylase sirtuin-2 in liver metabolic stress through regulating pyruvate kinase M2 ubiquitination

NAD-dependent deacetylase Sirt2 is involved in mammalian metabolic activities, matching energy demand with energy production and expenditure, and is relevant to a variety of metabolic diseases. Here, we constructed Sirt2 knockout and adeno-associated virus overexpression mice and found that deletion of hepatic Sirt2 accelerated primary obesity and insulin resistance in mice with concomitant hepatic metabolic dysfunction. However, the key targets of Sirt2 are unknown. We identified the M2 isoform of pyruvate kinase (PKM2) as a key Sirt2 target involved in glycolysis in metabolic stress. Through yeast two-hybrid and mass spectrometry combined with multi-omics analysis, we identified candidate acetylation modification targets of Sirt2 on PKM2 lysine 135 (K135). The Sirt2-mediated deacetylation-ubiquitination switch of PKM2 regulated the development of glycolysis. Here, we found that Sirt2 deficiency led to impaired glucose tolerance and insulin resistance and induced primary obesity. Sirt2 severely disrupted liver function in mice under metabolic stress, exacerbated the metabolic burden on the liver, and affected glucose metabolism. Sirt2 underwent acetylation modification of lysine 135 of PKM2 through a histidine 187 enzyme active site-dependent effect and reduced ubiquitination of the K48 ubiquitin chain of PKM2. Our findings reveal that the hepatic glucose metabolism links nutrient state to whole-body energetics through the rhythmic regulation of Sirt2.

Index Development to Comprehensive Assess Liver Function during the Dairy Cows’ Transition Period in Low-Tropic Conditions

The aim of this work was to develop a liver tissue function index during the transition period of dairy cows managed in low-tropic conditions. In two farms, twenty crossbred and synthetic native cows during the peripartum period were selected, and blood samples were taken on days −30 and −15 prepartum, the calving day, and 7, 20, 35, 50, 65, 80 and 105 days postpartum for serum metabolic tests. On each measurement day, body condition scores (BCS) and parameters on nitrogen metabolism (total protein—TP, albumin—ALB, globulin—GLOB, urea), adipose tissue metabolism (cholesterol—COL, non-esterified fatty acids—NEFA) and two transaminases (alanine aminotransferase—ALT and aspartate aminotransferase—AST) were evaluated. Data analysis included the Spearman correlation, principal components, multiple linear regression and cluster analysis. Results showed that regarding the days after calving and BCS, a liver tissue function index can be constructed using the TP, urea, COL, ALT and NEFA. The estimated index generated three groupings, both by days after calving and BCS. In the former, the index discriminated the metabolic behavior in the prepartum, parturition and postpartum periods, while in the latter, the index discriminated between extreme (2.25, 2.50 and 4.25), slightly low (2.75 and 3.0) and slightly high (3.25 to 4) conditions. The results allow us to conclude that it is feasible to construct mathematical function indexes for liver function to monitor metabolic changes during highly demanding productive phases in dairy cows under tropical conditions.

Analysis of factors related to recanalization of portal vein thrombosis in liver cirrhosis: a retrospective cohort study

BackgroundPortal vein thrombosis (PVT) is a common complication of liver cirrhosis, yet there are fewer studies about predictors of PVT recanalization. We aimed to further explore the predictors of recanalization in cirrhotic PVT to facilitate accurate prediction of patients’ clinical status and timely initiation of appropriate treatment and interventions. To further investigate the benefits and risks of anticoagulant therapy in cirrhotic PVT patients.MethodsA retrospective cohort study of patients with cirrhotic PVT in our hospital between January 2016 and December 2022, The primary endpoint was to analyze predictors of PVT recanalization by COX regression. Others included bleeding rate, liver function, and mortality.ResultsThis study included a total of 82 patients, with 30 in the recanalization group and 52 in the non-recanalization group. Anticoagulation therapy was the only independent protective factor for portal vein thrombosis recanalization and the independent risk factors included massive ascites, history of splenectomy, Child-Pugh B/C class, and main trunk width of the portal vein. Anticoagulation therapy was associated with a significantly higher rate of PVT recanalization (75.9% vs. 20%, log-rank P < 0.001) and a lower rate of PVT progression (6.9% vs. 54.7%, log-rank P = 0.002). There was no significant difference between different anticoagulation regimens for PVT recanalization. Anticoagulation therapy did not increase the incidence of bleeding complications(P = 0.407). At the end of the study follow-up, Child-Pugh classification, MELD score, and albumin level were better in the anticoagulation group than in the non-anticoagulation group. There was no significant difference in 2-year survival between the two groups.ConclusionAnticoagulation, massive ascites, history of splenectomy, Child-Pugh B/C class, and main portal vein width were associated with portal vein thrombosis recanalization. Anticoagulation may increase the rate of PVT recanalization and decrease the rate of PVT progression without increasing the rate of bleeding. Anticoagulation may be beneficial in improving liver function in patients with PVT in cirrhosis.

The Effect of Mobile Lifestyle Intervention Combined with High-Protein Meal Replacement on Liver Function in Patients with Metabolic Dysfunction-Associated Steatotic Liver Disease: A Pilot Randomized Controlled Trial

While many studies have explored dietary substitutes and mobile apps separately, a combined approach to metabolic dysfunction-associated steatotic liver disease (MASLD) has not been investigated. This study evaluated short-term mobile interventions coupled with partial meal replacement in patients with MASLD. Sixty adults with MASLD and a body mass index ≥25 kg/m2 from a health examination center were randomized into an intervention group using a mobile app with partial meal replacements or a control group receiving standard educational materials. Liver enzyme levels, lipid profiles, and anthropometric measurements were assessed at baseline and after 4 weeks. Twenty-five participants in the intervention group and 24 in the control group completed the trial. Significant reductions were observed in the intervention group for alanine aminotransferase (−28.32 versus [vs.] −10.67, p = 0.006) and gamma-glutamyl transferase (−27.76 vs. 2.79, p = 0.014). No significant changes in aspartate aminotransferase, body weight, or waist circumference were noted in the intervention group. Four weeks of mobile lifestyle intervention incorporating partial meal replacements improved liver enzyme profiles in patients with MASLD. This strategy demonstrated the potential for mitigating elevated liver enzyme levels without altering body weight or waist circumference. Comprehensive and longer-term research is needed to substantiate and elaborate these preliminary outcomes.

GPR116 alleviates acetaminophen-induced liver injury in mice by inhibiting endoplasmic reticulum stress

BackgroundAcetaminophen (APAP) overdose is a significant contributor to drug-induced liver injury worldwide. G-protein–coupled receptor 116 (GPR116) is an important homeostatic maintenance molecule in the body, but little is known about its role in APAP-induced liver injury (AILI).MethodsGPR116 expression was determined in both human and mouse AILI models. Hepatic function and damage response were analyzed in hepatocyte-specific GPR116 deletion (GPR116△HC) mice undergoing APAP challenge. RNA-sequencing, immunofluorescence confocal, and co-immunoprecipitation (CO-IP) were employed to elucidate the impact and underlying mechanisms of GPR116 in AILI.ResultsIntrahepatic GPR116 was upregulated in human and mice with AILI. GPR116△HC mice were vulnerable to AILI compared to wild-type mice. Overexpression of GPR116 effectively mitigated AILI in wild-type mice and counteracted the heightened susceptibility of GPR116△HC mice to APAP. Mechanistically, GPR116 inhibits the binding immunoglobulin protein (BiP), a critical regulator of ER function, through its interaction with β-arrestin1, thereby mitigating ER stress during the early stage of AILI. Additionally, the activation of GPR116 by ligand FNDC4 has been shown to confer a protective effect against early hepatotoxicity caused by APAP in murine model.ConclusionsUpregulation of GPR116 on hepatocytes inhibits ER stress by binding to β-arrestin1, protecting mice from APAP-induced hepatotoxicity. GPR116 may serve as a promising therapeutic target for AILI.

Importance of Blood Glucose Measurement for Predicting the Prognosis of Long COVID: A Retrospective Study in Japan

Purpose: The present study aimed to clarify the effects of a hyperglycemic condition on the clinical consequences of long COVID. Methods: Among 643 patients who visited the outpatient clinic of our hospital from February 2021 to September 2023, long COVID patients were classified into a hyperglycemic (HG) group with casual blood glucose levels above 140 mg/dL and a normoglycemic (NG) group. The patients’ backgrounds, clinical symptoms, health status including the QOL evaluation scale (EQ-5D-5L), self-rating depression scale (SDS), and F-scale questionnaire (FSSG), blood test data, and recovery periods were analyzed. Results: The NG group included 607 patients with long COVID and the HG group included 36 patients with long COVID. Patients in the HG group were older than those in the NG group (55 vs. 41 years; p &lt; 0.001) and included a larger percentage of males (67% vs. 44%; p = 0.009). The HG group had a larger percentage of patients with moderate-to-severe conditions in the acute infection phase (28% vs. 12%; p = 0.008), a higher BMI (25 vs. 22 kg/m2; p &lt; 0.001), higher blood pressure (138/81 vs. 122/72 mmHg; p &lt; 0.001), and a larger percentage of patients with an alcohol drinking habit (53% vs. 34%; p = 0.031). Long COVID symptoms and self-rated scales were not differed between the two groups; however, the laboratory data showed that liver and renal functions and metabolic data were significantly worse in the HG group. Although there was no apparent difference between the two groups in duration from the infection to the first visit, the HG group had a significantly longer period of recovery from long COVID (median period of 421 vs. 294 days; p = 0.019). Conclusion: A hyperglycemic state associated with other lifestyle-related diseases is associated with the prolongation of recovery from long COVID.

Hepatoprotective Effect of Ethanolic Pomegranate Peel Extract Against Levofloxacin via Suppression of Oxidative Stress, Proinflammation, and Apoptosis in Male Rats.

One of the fluoroquinolone antibiotics, levofloxacin (LEV), is used to treat a variety of illnesses leading to oxidative stress and cellular damage. Peel from Punica granatum is a waste product abundant in phytochemicals with various biological activities. This study aimed to evaluate P. granatum peel extract's (PGPE) potential to mitigate oxidative stress, inflammation, apoptosis, and liver damage caused by LEV. There were four groups of rats: control, PGPE, LEV, and PGPE + LEV, respectively, and they were orally administered their daily treatments for 2 weeks. Results revealed that PGPE has a large number of phytochemical components with high antioxidant activity. PGPE intake alone enhanced the antioxidant status and decreased oxidative stress. On the other hand, pretreatment of the LEV group with PGPE restored oxidative stress, antioxidant enzymes, glutathione content, liver function biomarkers, and hematological parameters. Also, normalization of gene expressions (cyclooxygenase-2, transforming growth factor-beta1, caspase-3, heme oxygenase-1, B cell lymphoma-2, interleukin [IL]-10, and IL-1) and improvement in liver architecture, and immunohistochemical alpha-smooth muscle actin, were seen in comparison to the LEV group. Conclusively, PGPE exhibits strong anti-inflammatory, antiapoptotic, and antioxidant properties that shield rat liver from the damaging effects of LEV and offer a fresh viewpoint on the application of fruit waste products.

A Randomized Controlled Trial of the Safety and Efficacy of Systemic Enzyme Supplementation on Symptoms and Quality of Life in Patients with Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) imposes a substantial symptom burden that adversely impacts patients’ quality of life. Current anti-fibrotic treatments for IPF provide limited symptomatic relief, necessitating the implementation of complementary disease management strategies to enhance health-related quality of life (HRQOL). Serracor-NK® and Serra Rx260, systemic enzyme supplements, improved symptoms and HRQOL with favorable safety profiles in a proof-of-concept study in PF patients. This prospective, double-blind randomized placebo-controlled trial enrolled 100 IPF patients from six institutions. The supplement group (n = 50) received the oral systemic enzyme supplements Serracor-NK® and Serra Rx260 in addition to standard care for 6 months, while the placebo group (n = 50) received standard care alone. The primary objective was to evaluate the regimen’s impact on symptoms, QOL, and well-being using the UCSD shortness of breath (UCSD-SOB) questionnaire, St. George’s respiratory questionnaire (SGRQ), and WHO well-being index (WHO-5). Safety evaluation was a secondary objective. A significantly higher proportion of patients in the supplement group demonstrated meaningful improvement in symptoms as compared to the placebo group, as assessed by the UCSD-SOB (p &lt; 0.05) and SGRQ questionnaires (p &lt; 0.05). Additionally, a significantly greater proportion of patients in the supplement group showed improved QOL and well-being (p &lt; 0.05) and reduced health impairment (p &lt; 0.05), as assessed by SGRQ. Mental well-being (WHO-5) and physical activity (SGRQ activity domain) did not differ significantly between the groups. Safety assessments, including liver function tests and vital signs, indicated that the supplement regimen was well tolerated. To conclude, Serracor-NK® and Serra Rx260 alleviate symptoms and enhance HRQOL in IPF patients with a favorable safety profile (Clinical Trials Registry India registration number: CTRI/2020/05/025374).

Effects of abomasal infusion of branched-chain amino acids or branched-chain keto-acids on liver function, inflammation, and oxidative stress in multiparous fresh cows

Reduced liver function, increased oxidative stress, and inflammation in early lactation negatively impact lactation performance and health of fresh cows. Previous findings from our group demonstrated that branched-chain amino acids (BCAA) infusion improved lactation performance and branched-chain ketoacids (BCKA) infusion decreased liver triglyceride (TG) in fresh cows. The objectives of this study were to determine the effect of BCAA and BCKA on blood and liver biomarkers of liver function, oxidative stress, and inflammation as well as expression of genes regulating inflammation and antioxidant metabolism in the liver. Thirty multiparous Holstein cows were used in a randomized block design receiving continuous abomasal infusion for 21 d after parturition. Treatments (10 cows each) were control (CON), cows abomasally infused with 0.9% saline; BCA, cows abomasally infused with BCAA (67 g valine, 50 g leucine, and 34 g isoleucine); and BCK, cows abomasally infused with BCKA (77 g ketovaline, 57 g ketoleucine, and 39 g ketoisoleucine). All cows were randomly assigned to treatments after parturition and received the same diet throughout the experimental period. Blood was collected at 3, 7, 14, and 21 d postpartum for liver function, oxidative stress, and inflammation biomarker profiling. Liver was also harvested on 7, 14, and 21 d postpartum for quantification of glutathione, protein carbonylation, and expression of genes. ANOVA was conducted for all data using PROC GLIMMIX in SAS. No treatment differences were observed for liver function biomarkers (bilirubin, gamma-glutamyl transferase, and aspartate aminotransferase). Cows receiving BCAA had lower blood NO2- and NO3- concentrations compared with CON. A tendency for lower advanced oxidized protein products was also observed in BCA cows compared with CON. Additionally, on d 7, BCA cows had lower protein carbonylation in the liver compared with CON. In contrast, BCK cows had higher plasma thiol and albumin, as well as liver reduced and total glutathione compared with CON cows. Compared with CON, BCK cows had higher expression glutathione reductase in the liver. Overall, these results suggest favorable alterations in oxidative stress and inflammation status in fresh cows receiving BCAA or BCKA infusion during the first 3 weeks of lactation, which likely contributed to previously-observed changes in lactation performance and liver TG concentrations. Future work is required to evaluate the interrelated metabolism of BCAA and BCKA to better understand their effects on oxidative and immune metabolism.

Serum lipidomic profiling of dairy calves fed milk replacers containing animal or vegetable fats

Vegetable fat blends are commonly used as fat sources in milk replacers (MR) for calves, but their composition differs considerably from that of bovine milk fat. The aim of this study was to investigate the serum lipid profile of pre-weaned calves fed twice-daily MR containing 30% fat (% DM). Upon arrival, 30 male Holstein-Friesian calves (BW = 45.6 ± 4.0 kg, age = 2.29 ± 0.8 d) were randomly assigned to 2 experimental diets (n = 15 per treatment): one MR was derived from either vegetable fats (VG; 80% rapeseed and 20% coconut fats) or animal fats (AN; 65% Packer's lard and 35% dairy cream). The 2 MR formulas contained 30% fat, 24% CP, and 36% lactose. Calves were housed indoors in individual pens with ad libitum access to chopped straw and water. Daily milk allowances were 6.0 L from d 1 to 5, 7.0 L from d 6 to 9, and 8.0 L from d 10 to 35, divided into 2 equal meals and prepared at 13.5% solids. An untargeted liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) method was employed to analyze the lipid profiles in the serum of calves sampled from the jugular vein at 35 d of age. In total, 594 lipids were characterized, comprising 25 different lipid classes. Principal component analysis (PCA) showed significant separation between VG and AN, indicating different lipid profiles in the serum. An orthogonal partial least squares discriminant analysis (OPLS-DA) classification model was used to further validate the distinction between the 2 treatment groups. The model exhibited a robust class separation and high predictive accuracy. Using a Volcano plot (fold change threshold ≥1.5 and false discovery rate ≤0.05), it was observed that calves fed AN had higher levels of 39 lipid species in serum than calves fed VG, whereas 171 lipid species were lower in the AN group. Lipid classes, such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), sphingomyelin (SM), triglycerides (TG), lysophosphatidylcholine (LPC), and lysophosphatidylethanolamine (LPE), were different. In particular, PC and PE were observed at lower levels in calves fed AN, possibly indicating shifts in cell membrane characteristics, intracellular signaling, and liver functions. In addition, a decrease in certain triglyceride (TG) species was observed in calves fed AN, including a decrease in TG species such as TG 36:0 and TG 38:0, possibly related to variations in the content of certain fatty acids (FA) within the AN MR, such as C10:0, C12:0, C14:0, and C18:0 compared with the VG MR. Calves fed AN had lower levels of LPC and LPE, and lyso-phosphatidylinositol (LPI), SM, and phosphatidylinositol (PI) species than calves fed VG, suggesting shifts in lipoprotein and lipid metabolic pathways. In conclusion, these results deepen the understanding of how lipid sources in MR can modulate the serum lipidome profiles of dairy calves.

The Centennial Allograft: Cumulative Kidney and Liver Function for More Than 100 Years

The maximum cumulative life span of kidneys and livers first in donors and then in transplant recipients has not been established. The purpose of this study was to determine if cumulative organ function for more than 90 years is possible for transplanted kidneys and livers. This study included kidney and liver transplants from living or deceased donors ≥55 years. Cumulative organ function (COF) = Organ Age at Donation [Years] + Tx Allograft Function [Years]. Univariate and multivariable methods were used to describe characteristics and outcomes. Between 1987 and 2022, a total of 81,807 kidney and 37,099 liver transplants were included in this study. Of all kidney grafts 2.7% but 16.6% of all liver grafts reached the 90-year COF mark. There were only 2 living donor kidneys that surpassed the 100-year mark versus 29 deceased liver grafts. The longest kidney function was 104 years and longest liver function 108 years. Multivariate analysis showed that optimal donor and recipient selection and management are predictors for allograft longevity. COF in organs exceeding 100 physiologic years is possible. Extended organ longevity was 5 times more common for livers than kidneys. These analyses support that age alone should not exclude older kidney and liver donors from consideration for transplantation.

Revisiting Mac-2-Binding Protein Glycosylation Isomer (M2BPGi) for Diagnosing High-Risk Liver Fibrosis in Chronic Hepatitis B Patients: A Stepwise Diagnostic Analysis

Abstract* Background The level of liver fibrosis is the basis for the treatment of chronic hepatitis B (CHB), and it is necessary to adapt non-invasive liver fibrosis modalities. We aimed to investigate the use of M2BPGi as a single or combined diagnostic modality for liver fibrosis in CHB patients through a stepwise diagnostic analysis. Methods Cross-sectional data were taken from patients between October 2021 and August 2022. Demographic data, blood profile, liver function, and liver stiffness were measured in CHB patients over 18 years old, willing to take part in the research, and had complete data. APRI, FIB-4, and AAR were calculated using the well-known formulas. Serum M2BPGi-levels were converted into a cut-off index (COI). The patients were divided into low-risk (LR) and high-risk fibrosis (HR) groups. A cut-off for each predictor variable to differentiate between the LR and HR groups was determined. The obtained cut-off was assessed for its association with the grouping of liver elastography results. Models to diagnose the liver stiffness measurement (LSM) ≥8 kPa were created and compared through multivariate and ROC analyses. Results The number of patients that met the inclusion and exclusion criteria was 143 (HR = 65, LR = 78). The cut-off for diagnosing LSM ≥8kPa was 0.311, 0.742, 0.635, and 1.434 for APRI, FIB-4, AAR, and M2BPGi, respectively. This cut-off was significantly associated with the results of the HR and LR groupings. A multivariate analysis found that FIB4, AAR, and M2BPGi added significantly to the model. Statistically, the most optimal use of M2BPGi was combined with FIB-4, with an AUC of 0.835. Conclusions The optimal cut-off of M2BPGi for diagnosing high-risk liver fibrosis in this study was 1.434. M2BPGi should be used with FIB-4 as a diagnostic tool for diagnosing liver fibrosis, especially in the absence of a liver biopsy or elastography.

In vivo evaluation by oral administration of chitosan combined with bioactive glass against cadmium-induced toxicity in rats

Bioactive glass and chitosan are biomaterials widely used for orthopedic applications, notably as bone grafts. Although these biomaterials show promising therapeutic properties, no research has yet examined their potential for oral administration in soft tissue protection, particularly against metal toxicity. The aim of our study was to evaluate the potential of chitosan from cuttlefish (CHS) bone combined with bioactive glass (BG) against Cadmium-induced toxicity in rats. Cadmium (Cd), a heavy metal that accumulates in tissues, causes various disorders. Experiments were carried out on rats intoxicated acutely by oral administration of Cd (20 mg/kg body weight) and/or concomitantly with oral administration of CHS/BG (100 mg/kg body weight) for 7 days. Using pathophysiological and biochemical tests, we evaluated the detoxifying effect of orally administered CHS/BG against Cd toxicity. Our results showed, for the first time, a significant detoxifying effect of CHS/BG against Cd-induced toxicity in rats. Treatment with CHS/BG protected rats against the harmful effects of Cd by reducing lipid peroxidation levels and enhancing antioxidant enzyme activities. In addition, it helped restore phosphocalcic balance and protect liver, kidney and brain function. Remarkably, it also reduced Cd levels in the liver, kidneys and brain, as well as in the bones of rats. These results show that oral administration of CHS/BG has a strong therapeutic potential on tissues through detoxification of cadmium-exposed rats.

In vivo turnover and biodistribution of soluble AXL: implications for biomarker development

Soluble biomarkers are paramount to personalized medicine. However, the in vivo turnover and biodistribution of soluble proteins is seldom characterized. The cleaved extracellular domain of the AXL receptor (sAXL) is a prognostic biomarker in several diseases and a predictive marker of AXL targeting agents. Plasma sAXL reflects a balance between production in tissues with lymphatic transport into the circulation and removal from blood by degradation or excretion. It is unclear how this transport cycle affects plasma sAXL levels that are the metric for biomarker development. Radiolabeled mouse sAxl was monitored after intravenous injection to measure degradation and urinary excretion of sAxl, and after intradermal injection to mimic tissue or tumor production. sAxl was rapidly taken-up and degraded by the liver and kidney cortex. Surprisingly, intact sAxl was detectable in urine, indicating passage through the glomerular filter and a unique sampling opportunity. The structure of sAxl showed an elongated, flexible molecule with a length of 18 nm and a thickness of only 3 nm, allowing passage through the glomerulus and excretion into the urine. Intradermally injected sAxl passed through local and distant lymph nodes, followed by uptake in liver and kidney cortex. Low levels of sAxl were seen in the plasma, consistent with an extended transit time from local tissue to circulation. The rapid plasma clearance of sAxl suggests that steady-state levels in blood will sensitively and dynamically reflect the rate of production of sAxl in the tissues but will be influenced by perturbations of liver and kidney function.