Liver Function Research Articles

Unveiling the Interplay: Antioxidant Enzyme Polymorphisms and Oxidative Stress in Preterm Neonatal Renal and Hepatic Functions.

To explore the relationship between oxidative stress biomarkers and the occurrence of acute kidney injury (AKI) alongside notable liver function disturbances in preterm neonates. Given the immaturity of kidneys and incomplete liver development in preterm neonates, oxidative stress poses a considerable threat to their renal and hepatic health. To find out the association between various oxidative stress biomarkers and polymorphisms of antioxidant enzymes with renal and live functions. In this cross-sectional study, we gathered umbilical cord blood and peripheral blood samples for assessing oxidative stress biomarkers and identifying single nucleotide polymorphisms (SNPs) in antioxidant enzymes. Utilizing enzyme-linked immunosorbent assay kits, we quantified these oxidative stress biomarkers. Receiver-operating characteristics curve analysis was employed to ascertain the predictive capacity of these biomarkers, denoted by the area-under-the-curve (AUC). Our findings revealed that umbilical cord heat-shock proteins emerged as robust predictors of neonatal AKI (AUC: 0.92; 95% CI: 0.8-1) with a defined cut-off concentration of 1.8 ng/mL. Likewise, umbilical cord 8-hydroxy-2-deoxy guanosine demonstrated significant predictability for liver function alterations (AUC: 0.7; 95% CI: 0.6-0.9) at a cut-off concentration of 2487.6 pg/mL. We observed significant associations between SNPs in endothelial nitric oxide synthase and catalase with both AKI and impaired liver functions. Prospective studies are warranted to validate these findings, with a particular focus on exploring potential antioxidant interventions aimed at mitigating AKI and liver function abnormalities.

Vibrio vulnificus infection complicated by acute-on-chronic liver failure: A case report

Rationale: Vibrio vulnificus is a gram-negative bacterium that can cause 3 clinical syndromes: gastrointestinal symptoms, skin septicemia, and primary septicemia. V vulnificus infection can induce an exacerbation of liver disease, eventually requiring intensive care for multiorgan failure. Patient concerns: A 56-year-old Chinese male who was admitted for left lower limb swelling 5 days after sustaining an injury. His left lower leg was wounded with a machete used for cutting rubber. Notably, this machete had also been previously utilized for cutting seafood. Blood culture results indicated the presence of V vulnificus during the hospitalization. The patient’s condition deteriorated rapidly leading to acute liver failure. Over the ensuing days, the patient experienced separation of tendency of aminotransferase and bilirubin (bilirubin-aminotransferase dissociation), indicative of worsening liver function. Of note, the patient had a history of untreated hepatitis B virus infection and a long drinking history. Diagnoses: Acute-on-chronic liver failure following a V vulnificus infection. Interventions: We utilized double plasma molecular adsorption system (DPMAS) to address the deterioration of the patient’s liver function. Outcomes: After 2 DPMAS treatments, the patient’s liver function showed improvement. Lessons: This report underscores the importance of timely and repeated DPMAS treatment of patients with a drinking history or chronic liver disease when they present with V vulnificus septicemia.

Hemophagocytic lymphohistiocytosis: pediatric hepatic perspective

BackgroundHepatic manifestations of hemophagocytic lymphohistiocytosis (HLH), an underrecognized primary presentation in pediatric age group, mandate high levels of suspicion for early diagnosis.AimThis is to study the frequencies of clinical and laboratory hepatic involvement in patients with familial/primary or secondary/acquired HLH in relation to disease reactivation and outcome.MethodsA 6-month retrospective cohort study recruited 35 patients with HLH. Detailed clinical, laboratory, and genetic characteristics of HLH were collected. Hepatic transaminases and synthetic liver functions were collected at presentation, weeks 2 and 8 after starting treatment, and at time of reactivation. Biochemical liver involvement was considered when alanine aminotransferase (ALT) lived three-times more than the upper normal level. Overall (OS) and reactivation free survival were analyzed according to liver involvement.ResultsTwenty patients (57%) had genetically confirmed HLH, 12 (34.3%) had MUNC13D mutations, 3 (8.5%) had STXBP2 mutations, and 5 (14.3%) had RAB27A mutations, while 9 (25.7%) had no genetic mutations with 4 of them had secondary HLH. Six patients (17.2%) patients had unknown genetics status. Median (IQR) age of the whole group was 18 months (6–36) with an age range of 2–108 months. Liver enlargement was detected at diagnosis in 29 (82.9%) and at reactivation in 18 (51.4%) patients. Eight (22.86%) patients had biochemical hepatic involvement at presentation with no significant difference in their demographic, initial clinical presentation, survival, or the type of mutant gene according to liver involvement.ConclusionVariable hepatic biochemical involvement might be the presenting manifestation of HLH at diagnosis and upon reactivation, yet it did not impact disease outcome.

Protective effects of Khaya senegalensis stem bark extracts against acetaminophen-induced oxidative damage, dyslipidaemia, and hepatotoxicity in rats

Background Free radical attacks have been implicated in the aetiology of many diseases and several plants are used traditionally for the management of many oxidative-stress related diseases. Khaya senegalensis is used traditionally for the management diseases such as diabetes and for the treatment of infections. However, mechanisms underlying actions of K. senegalensis are poorly understood. Purpose This study aimed at the preliminary determination of the phytochemical constituents and investigation of the antioxidative and hepatoprotective actions of K. senegalensis in acetaminophen-treated rats. Method Aqueous extracts of K. senegalensis were screened for the presence of key phytochemicals. Total flavonoid and phenolic contents were quantified. Wistar albino rats were pre-treated with saline (control) or graded concentrations of K. senegalensis (50 – 200mg/kgbw) for 10 days prior to acetaminophen (2g/kg body weight) administration. Serum levels of vitamin C, thiobarbituric reactive substances, catalase activities, enzyme markers of liver function were assessed. Cholesterol-phospholipid ratio in treated-rats were determined. Results K. senegalensis extract showed the presence of saponins, tannins, cardiac glycosides, alkaloids, flavonoids and phenolic compounds. Total phenolic and total flavonoid contents were determined as 57.14±0.85mgQE/g and 51.72±0.77mgGE/g. Acetaminophen (2g/kg bw) raised serum TBARS (4.7-fold, P<0.001), H2O2 levels (2.3-fold, P<0.001), AST (5.9-fold, P<0.001), ALT (6.6-fold, P<0.001) and ALP (4.2-fold, P<0.001) and reduced serum levels of vitamin C (54%, P<0.001) and catalase activity (74.6%, P<0.001). Treatment of K. senegalensis extracts inhibited effects of acetaminophen on TBARS (18.2% - 46.4%, P<0.05 – 0.001), vitamin C (1.4 – 1.8-fold, P<0.001 – 0.05), H2O2 levels (19.1 – 50.1%, P<0.001-0.05), catalase activities (1.4 – 3.1-fold, P<0.001 – 0.05), AST (27.7 – 62.8%, P<0.001 – 0.05), ALT (35.6 – 57.5%, P<0.001 – 0.05) and ALP (15.9 – 46.2%, P<0.01 – 0.05). The extract reduced cholesterol-phospholipid ratio (21 – 31%, P<0.05). Conclusion These results motivate further development of the therapeutic potential of K. senegalensis

The liver fibrosis-8 index is a predictor for all-cause mortality in cardiovascular disease patients: A cohort study.

Participants with cardiovascular diseases (CVD) often exhibit liver function abnormalities, hepatic fibrosis and cirrhosis. The extent of liver fibrosis is closely related to the prognosis of CVD. However, the association between the liver fibrosis-8 (FIB-8) index, a marker of liver fibrosis, and all-cause mortality in CVD participants remains unclear. This study aims to investigate the relationship between the FIB-8 index and all-cause mortality among individuals with CVD. A total of 1727 CVD American participants were enrolled from the National Health and Nutrition Examination Survey (NHANES) spanning from 1999 to 2018. Initially, we constructed weighted COX regression models and performed sensitivity analyses to examine the correlation between the FIB-8 index and all-cause mortality in CVD participants. Subsequently, we employed restricted cubic spline (RCS) to visualize their linear relationship. Finally, the stratified analyses and interaction tests of covariates were performed and presented in the forest plot. A total of 1727 participants were included in our study, with a mean age of 61.68 ± 0.47 years, with men accounting for 59.19%. After adjustment for relevant covariables, weighted COX regression models indicated that the hazard ratio (HR) and 95% confidence interval (95% CI) for the association between the FIB-8 index and all-cause mortality in CVD participants was 1.21 (1.12, 1.30). Sensitivity analysis was then conducted, revealing that the results remained stable. In fully adjusted model, individuals in quartiles 3 and 4 demonstrated significant statistical differences compared to the lowest FIB-8 index quartile, with HR (95% CI) values of 1.88 (1.23, 2.87) and 2.17 (1.33, 3.53), respectively. Subsequently, RCS showed a linear relationship between the FIB-8 index and all-cause mortality among CVD participants. Finally, the interaction test revealed that no other covariables had significant interactions with the FIB-8 index in this study. A positive and linear correlation was observed between the FIB-8 index and all-cause mortality among CVD adult participants in NHANES from 1999 to 2018. Our findings indicated that the FIB-8 index could serve as an excellent indicator for assessing all-cause mortality within the CVD population. The lower the FIB-8 index, the lower the all-cause mortality among CVD participants.

A compact machine perfusion device for whole blood perfusion in isolated rat liver.

We established a compact machine perfusion system for whole blood perfusion of rat liver by making use of oxygenation filters as an artificial lung. Livers removed from rats were divided into Krebs-Henseleit (control), 50% blood (hemoglobin: 7g/dL), and whole blood (hemoglobin: 14g/dL) groups, then perfused (total perfusate volume: 25ml) with a small oxygenation filter at 37°C for 120min. Blood or perfusate was collected over time, and blood gas and blood cell were measured. In addition, bile volume and portal venous pressure measurements were taken. In all groups, the partial pressure of oxygen was controlled to approximately 400mmHg. Flow rates were maintained at approximately about 20-30ml/min according to liver size. Portal venous pressure was normal in the 50% blood and whole blood groups, while lower than the reference value in the Krebs-Henseleit group. Twice as much bile was produced in the 50% blood and whole blood groups relative with the Krebs-Henseleit group. We observed no differences in hemoglobin and red blood cell levels. Lactate levels were normal in the 50% blood and whole blood groups, but were elevated in the Krebs-Henseleit group. Our compact perfusion system using oxygenation filters was able to maintain rat liver function by perfusing a small amount of extracorporeal blood. This system is simple and stable, and may contribute to the future development of machine perfusion systems.

Impact of Etiology on Efficacy Outcomes with Atezolizumab Plus Bevacizumab in Patients with Advanced Hepatocellular Carcinoma: A Multinational Retrospective Analysis in Asia-Pacific.

Atezolizumab-bevacizumab is a standard first-line treatment for unresectable hepatocellular carcinoma (uHCC). Given the diversity in HCC etiology and its potential impact on the tumor microenvironment, understanding how different liver disease etiologies affect treatment efficacy is important. We assessed the influence of liver disease etiology on the efficacy of atezolizumab-bevacizumab and evaluated changes in liver function during treatment with atezolizumab-bevacizumab. This study included 390 patients with uHCC treated with first-line atezolizumab-bevacizumab from Asan Medical Center, South Korea, and National Cancer Centre Singapore, Singapore from July 2016 to March 2023. Patients were classified to viral, metabolic dysfunction-associated liver disease (MASLD) and nonviral/non-MASLD groups. Albumin-bilirubin (ALBI) scores were recorded at baseline and every two cycles up to cycle six and at the time of disease progression. The majority of patients presented with viral etiologies (74.1%), and 17.2% had MASLD. Across etiological groups (viral versus MASLD versus nonviral/non-MASLD) no significant differences in objective response rate (23.2% versus 29.9% versus 23.5%, respectively; p = 0.515), progression-free survival (median 5.4 versus 7.7 versus 6.0 months; p = 0.320), and overall survival (18.1 versus 18.9 versus 14.4 months; p = 0.400) were observed. Among the patients with disease progression, ALBI scores at the time of progression were significantly higher than at baseline. Subsequent therapy was administered significantly less often to patients with ALBI grade 3 at disease progression compared with those with ALBI grades 1 or 2 (48.4% versus 78.8%, p = 0.002) CONCLUSIONS: Atezolizumab-bevacizumab demonstrates consistent efficacy regardless of HCC etiology, supporting its use as a first-line treatment across diverse patient populations. Liver function assessments remain crucial for managing therapy and predicting outcomes.

Acetaminophen Overdose Reveals PAR4 as a Low-Expressing but Potent Receptor on the Hepatic Endothelium in Mice.

The protease thrombin, which elicits multiple physiological and pathological effects on vascular endothelial cells (ECs), can signal through PARs (protease-activated receptors) 1 and 4. PAR1 is a high-affinity thrombin receptor known to signal on ECs, whereas PAR4 is a low-affinity thrombin receptor, and evidence for its expression and function on ECs is mixed. This study aims to exploit the high levels of thrombin generation and hepatic vascular dysfunction that occur during acetaminophen (APAP) overdose to determine (1) whether hepatic endothelial PAR4 is a functional receptor, and (2) the endothelial-specific functions for PAR1 and PAR4 in a high thrombin and pathological setting. We generated mice with conditional deletion of Par1/Par4 in ECs and overdosed them with APAP. Hepatic vascular permeability, erythrocyte accumulation in the liver, thrombin generation, and liver function were assessed following overdose. Additionally, we investigated the expression levels of endothelial PARs and how they influence transcription in APAP-overdosed liver ECs using endothelial translating ribosome affinity purification followed by next-generation sequencing. We found that mice deficient in high-expressing endothelial Par1 or low-expressing Par4 had equivalent reductions in APAP-induced hepatic vascular instability, although mice deficient for both receptors had lower vascular permeability at an earlier timepoint after APAP overdose than either of the single mutants. Additionally, mice with loss of both endothelial Par1 and Par4 had reduced thrombin generation after APAP overdose, suggesting decreased hypercoagulability. Last, we found that endothelial PAR1-but not PAR4-can regulate transcription in hepatic ECs. Low-expressing PAR4 can react similarly to high-expressing PAR1 in APAP-overdosed hepatic ECs, demonstrating that PAR4 is a potent thrombin receptor. Additionally, these receptors are functionally redundant but act divergently in their expression and ability to influence transcription in hepatic ECs.

Sulforaphane Improves Liver Metabolism and Gut Microbiota in Circadian Rhythm Disorder Mice Models Fed With High-Fat Diets.

This study aims to investigate the effect of sulforaphane (SFN) on hepatic metabolism and gut microbiota in a shifted circadian rhythm (CR) mouse model fed with a high-fat diet (HFD). A shifted CR mouse model with HFD is constructed. Biochemical analyses are used to evaluate the effects of SFN on lipid accumulation and liver function. Targeted metabolomics is used for liver metabolites. Results from hematoxylin and eosin staining and Oil Red O staining show that SFN improves liver lipid accumulation and intestinal inflammatory damage in shifted CR treatment with HFD. The concentrations of amino acid metabolites are increased, and the levels of bile acid metabolites are significantly decreased by SFN treatment. Results from 16S rRNA gene sequencing indicate that SFN modulates gut microbiota, particularly by enhancing beneficial bacteria such as Lachnospiraceae, Lactobacillus, Alistipes, Akkermansia, and Eubacteriaum coprostanoligenes. Correlation analysis confirms a close relationship between intestinal microbiota and hepatic metabolites. SFN significantly regulates CR protein expression in the hypothalamus and liver tissues. SFN alleviates hepatic metabolic disorder and gut microbiota dysbiosis induced by CR disruption under a high-fat diet in a mouse model, indicating the potential of SFN in regulating CR disruption.

Exploring the Dual Benefits of Fermented and Non-Fermented Garlic Powder on Growth, Antioxidative Capacity, Immune Responses, and Histology in Gray Mullet (Liza ramada)

This study investigated the effects of dietary garlic powder and fermented garlic powder supplementation at 1% and 2% levels on growth performance, digestive tract efficacy, blood biochemistry, immunity, and antioxidant status of Liza ramada (n = 225 fish; 86.00 ± 0.42 g) over a 60-day period. Fish fed diets supplemented with both forms of garlic at both levels exhibited significantly improved final body weight, weight gain, specific growth rate, and feed conversion ratio compared to the control group. Digestive enzyme activities (amylase, lipase, and protease) were significantly enhanced in all supplemented groups. Blood biochemical analysis revealed reduced glucose levels and increased total protein in garlic-supplemented groups, with no adverse effects on liver or kidney function markers. Immune parameters, including lysozyme activity, bactericidal activity against Streptococcus agalactiae, alternative complement pathway (ACP), and respiratory burst (NBT), were significantly enhanced in garlic-supplemented groups, with fermented garlic showing more pronounced effects. Antioxidant enzyme activities (SOD, CAT, and GPx) were also significantly increased in all supplemented groups, particularly in those fed fermented garlic. No significant differences in survival rates were observed among treatments. The results suggest that both garlic powder and fermented garlic powder supplementation, especially at the 2% level, can effectively improve growth, feed utilization, immune function, and antioxidant status in L. ramada. Fermented garlic generally demonstrated superior effects, indicating its potential as a beneficial feed additive in aquaculture. Based on these findings, it is recommended to incorporate fermented garlic powder at a 2% level in L. ramada diets to optimize growth performance and health status. Further research is warranted to investigate the long-term effects and cost-effectiveness of this supplementation strategy in commercial aquaculture settings.

Understanding the effect of acupuncture on nausea and vomiting during pregnancy from a metabolic perspective: study protocol for a single-blinded randomized controlled trial

BackgroundAcupuncture is an effective complementary therapy for nausea and vomiting during pregnancy (NVP). Nevertheless, the utilization of acupuncture for NVP has been minimally explored in current scholarly research, with a paucity of systematic randomized clinical trials (RCTs) in it. We aim to evaluate the effects of acupuncture on NVP after assisted reproductive techniques (ART) and explore the metabolism-related mechanism of the efficacy.MethodsThis single-blind, randomized, controlled trial will randomize 68 patients with NVP after ART to a traditional acupuncture (tACP) or a sham acupuncture (sACP) group. The tACP group will receive tACP thrice a week for 2 weeks with a day interval between sessions, while the sACP group will undergo the same number of nonpenetrative acupuncture at non-acupoints for the same period. Pregnancy-specific quantification of emesis will be used to evaluate symptom severity. Routine blood and urine tests, liver and kidney function tests, human chorionic gonadotropin, nuchal translucency thickness, and embryonic development measured using ultrasound will be used to evaluate safety during pregnancy. Non-targeted metabolomic analysis will be performed to explore the association between metabolic changes and clinical symptoms.DiscussionThis study will elucidate the effects and safety of acupuncture in treating NVP in women undergoing ART. The results of this study will contribute to optimizing acupuncture therapies by combining the body and auricular points and exploring the underlying therapeutic mechanism using a metabolomics approach.Trial registrationChinese Clinical Trial Registry, ChiCTR2300075259.

Clinicogenomic predictors of outcomes in patients with hepatocellular carcinoma treated with immunotherapy.

Immune checkpoint inhibitor (ICI) combinations extend overall survival (OS) while anti-PD-1/L1 monotherapy is non-inferior to sorafenib in treatment-naïve, patients with advanced hepatocellular carcinoma (HCC). Clinicogenomic features are posited to influence patient outcomes. The primary objective of this retrospective study was to define the clinical, pathologic, and genomic factors associated with outcomes to ICI therapy in patients with HCC. Patients with histologically confirmed advanced HCC treated with ICI at Memorial Sloan Kettering Cancer Center from 2012 to 2022 were included. Association between clinical, pathological, and genomic characteristics were assessed with univariable and multivariable Cox regression model for progression-free survival (PFS) and OS. Two-hundred and forty-two patients were treated with ICI-based therapy. Patients were predominantly male (82%) with virally mediated HCC (53%) and Child Pugh A score (70%). Median follow-up was 28 months (0.5-78.4). Median PFS for those treated in 1st line, 2nd line and ≥ 3rd line was 4.9 (range: 2.9-6.2), 3.1 (2.3-4.0), and 2.5 (2.1-4.0) months, respectively. Median OS for those treated in 1st line, 2nd line, and ≥ 3rd line was 16 (11-22), 7.5 (6.4-11), and 6.4 (4.6-26) months, respectively. Poor liver function and performance status associated with worse PFS and OS, while viral hepatitis C was associated with favorable outcome. Genetic alterations were not associated with outcomes. Clinicopathologic factors were the major determinates of outcomes for patients with advanced HCC treated with ICI. Molecular profiling did not aid in stratification of ICI outcomes. Future studies should explore alternative biomarkers such as the level of immune activation or the pretreatment composition of the immune tumor microenvironment.

A-111 “Activation” Of macro-ast by pyridoxal phosphate supplementation

Abstract Background Type 1 macro-AST is a high molecular weight AST (Aspartate Aminotransferase) formed between an AST monomer and immunoglobulins in plasma, which can cause elevated AST values. It is believed that reduced clearance or excretion of macro-AST can cause elevated AST results. Here we report a case of macro-AST that produced high AST values only by the AST assay that includes pyridoxal phosphate (PLP), not by the one without PLP. Case description A 54 year-old male patient diagnosed with disseminated Bartonellosis was monitored with ‘liver function” tests on a monthly basis, with AST varying between 24 to 73 U/L (Reference interval, 13-47 U/L). The patient’s AST value suddenly jumped to 378 U/L when the laboratory switched to an AST assay supplemented with PLP (named ASTPM) on Roche Cobas c702 analyzer (c702). When the same patient sample was tested using the previous AST assay which does not include PLP, a result of 14 U/L was obtained. Macro-AST was suspected, as all other “liver function” tests were within reference interval. Methods Protein-A and Protein-G were used to remove immunoglobulins from the patient sample and another sample with matching AST as a control, respectively. Three hundred microliters of washed Protein-A or Protein-G Sepharose bead slurry was mixed with 300 microliters of each sample, respectively. Each mixture was incubated at 37oC for 3 hours on a rocker. After centrifugation, the supernatant was transferred to a new tube. AST, ASTPM, and all other tests were performed on c702, and results corrected for dilution. The recovery of enzyme activity or immunoglobulin concentration after the removal of immunoglobulins was calculated, respectively. Results In the original sample, the ratio of ASTPM to AST was 28 (389 U/L vs. 14 U/L) for the patient, and 1.1 (304 U/L vs. 275 U/L) for the control. After the complete removal of immunoglobulin G (IgG), the recovery of ASTPM for the patient was 3% and for the control was 74%. The recovery of ALTPM (supplemented with PLP) was 89% for the patient and 85% for the control, showing the expected loss of enzymatic activity by Protein-A or Protein-G treatment. Conclusions The significant reduction of ASTPM activity (recovery of 3%) after removal of IgG in the patient sample proved that the AST enzyme was associated with IgG. The slight increase of ASTPM activity compared to AST (ratio of 1.1) in the control sample was an expected effect of supplementing PLP in the AST assay, however, the huge increase of ASTPM activity (ASTPM/AST ratio of 28) in the patient sample suggests that PLP “activated” the macro-AST and produced high AST result. This is a concerning effect of supplementing PLP in AST assays because it can cause spurious AST elevations in cases of macro-AST. As more laboratories begin to employ the PLP supplemented aminotransferase assays, it is important to acknowledge the interactions between PLP and macro-AST and the role of the laboratory to identify macro-AST in order to avoid unnecessary, costly, and time-consuming testing and procedures for these patients.

Clinical Efficacy of Autologous Bone Marrow Mesenchymal Stem Cell Transplantation for the Treatment of Patients with Refractory Cirrhotic Ascites

Objective: To analyze the efficacy of autologous bone marrow mesenchymal stem cell (BMSC) transplantation for the treatment of cirrhotic ascites (refractory). Methods: 64 patients with cirrhosis ascites (refractory) who were admitted to the hospital between May 2022 and April 2024 were selected and divided equally by random number table, the observation group was treated with BMSC autologous transplantation, and the reference group was treated with conventional medication, and the total effective rate, therapeutic indexes, liver and renal function indexes, and the change of urine volume were compared. Results: The total effective rate of the observation group was higher than that of the reference group (P < 0.05). Before treatment, there was no difference between the two groups in terms of therapeutic indexes such as depth of ascites, liver and kidney function indexes and 24-hour urine volume (P > 0.05). After treatment, the observation group’s ascites depth and other indicators were better than that of the reference group, liver and kidney function indicators were better than that of the reference group, and 24h urine volume was more than that of the reference group (P < 0.05). Conclusion: BMSC autotransplantation can improve the clinical efficacy of patients with cirrhosis ascites (refractory), accelerate the absorption of ascites, reduce the values of body mass and abdominal circumference, and protect the liver and kidney functions and increase the amount of urination.

Effects of microbe-derived antioxidants on growth performance, hepatic oxidative stress, mitochondrial function and cell apoptosis in weaning piglets

BackgroundWeaning causes redox dyshomeostasis in piglets, which leads to hepatic oxidative damage. Microbe-derived antioxidants (MA) have great potential for anti-oxidation. This study aimed to investigate changes in hepatic redox system, mitochondrial function and apoptosis after weaning, and effects of MA on growth performance and liver health in weaning piglets.MethodsThis study consisted of 2 experiments. In the both experiments, piglets were weaned at 21 days of age. In Exp. 1, at 21 (W0), 22 (W1), 25 (W4), 28 (W7), and 35 (W14) days of age, 6 piglets were slaughtered at each timepoint. In Exp. 2, piglets were divided into 2 groups: one received MA gavage (MA) and the other received saline gavage (CON). At 25 days of age, 6 piglets from each group were sacrificed.ResultsIn Exp. 1, weaning caused growth inhibition and liver developmental retardation from W0 to W4. The mRNA sequencing between W0 and W4 revealed that pathways related to “regulation of apoptotic process” and “reactive oxygen species metabolic process” were enriched. Further study showed that weaning led to higher hepatic content of reactive oxygen species (ROS), H2O2 and O2−. Weaning enhanced mitochondrial fission and suppressed their fusion, activated mitophagy, thus triggering cell apoptosis. In Exp. 2, MA improved growth performance of piglets with higher average daily gain (ADG) and average daily feed intake (ADFI). The hepatic ROS, as well as products of oxidative damage malonaldehyde (MDA) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the MA group decreased significantly than that of the CON group. The MA elevated mitochondrial membrane potential, increased activity of mitochondrial respiratory chain complexes (MRC) I and IV, enhanced mitochondrial fusion and reduced mitophagy, thus decreasing cell apoptosis.ConclusionsThe present study showed that MA improved the growth performance of weaning piglets and reversed weaning-induced oxidative damage, mitochondrial dysfunction, and apoptosis. Our results suggested that MA had promising prospects for maintaining liver health in weaning piglets and provided a reference for studies of liver diseases in humans.Graphical

A-093 Assessing Alkaline Phosphatase Reference Intervals Using Gamma-Glutamyl Transferase as a Surrogate for Normal Liver Function

Abstract Background There are limited published studies assessing reference intervals (RIs) for hepatic enzymes, particularly for alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT). In the US, ALP and GGT RIs were established on Roche assays using a European cohort of ≤ 450 patients that may not reflect population variance across practice settings. Further, age- and sex-specific variation in ALP and GGT may warrant tiered RIs, but evidence to justify this approach is limited. We aimed to evaluate the manufacturer’s RIs by comparing them to indirectly estimated RIs (IRIs) from routine clinical data. Methods 217,333 AST, ALT, ALP, and GGT results (Roche c702) performed between 1/1/2019-12/31/2022 on outpatients ≥21 years were extracted from the laboratory information system. The first ALP for each patient was identified, and the earliest AST, ALT, and GGT drawn within 7 days was included. This approach was repeated for GGT. Concordance and correlation were calculated using Weighted Cohen’s Kappa and Spearman’s rank correlation coefficient respectively. {refineR}, an algorithm for calculating IRIs, was applied to patients with “normal” liver function (defined as normal AST, ALT for all IRIs, plus normal GGT for ALP IRIs, and ALP for GGT IRIs). IRIs were estimated for all males, all females, females ≤50, and females >50 years and compared to the method specific manufacturer RI (ALP: 40-129 Units/L for males and 35-104 Units/L for females; GGT: 8-61 Units/L for males and 5-36 Units/L for females). Results Of the 71,783 outpatients, 54.9% were female, 74% self-identified as white and 19% as black. The median age was 58 (IQR: 43-68 years), the median ALP concentration was 77 (62-97 Units/L), and the median GGT concentration was 28 (17-57 Units/L). A moderate agreement between ALP and GGT was observed (Kappa = 0.48, 95% confidence interval: 0.46-0.51). A positive correlation between ALP and GGT was observed r = 0.51 (p<0.0001). For ALP, no significant differences were observed between the lower limit of the IRIs and the current RI. The upper limit of estimated IRIs was 132 [95% confidence interval: 117-147 Units/L] for patients with normal AST/ALT/GGT (n = 1596). For males, the sex-specific upper limit was 120 [101-140 Units/L] and for females, was 123 [110-136 Units/L]. Age stratified upper limits for females were 120 [101-140 Units/L], and 109 [97-121 Units/L] for ≤50 and >50 years, respectively. For GGT, no significant differences were observed for the lower limits. The upper limit for all patients with normal AST/ALT/ALP (n = 2,446) was 62 [55-70 Units/L]. For males, all females, females ≤50 and >50 years was 58 [46-69 Units/L], 40 [39-51 Units/L], 31 [23-39 Units/L], and 56 [41-71 Units/L]. Conclusions For the majority of patient subsets, the manufacturer RI agreed well with the IRIs. However, significant differences in IRIs were observed for the upper limit of ALP IRIs of all females with normal hepatobilliary function and in GGT for all females and females >50 years. Further investigation of the impact of preselecting patient populations on IRI estimation and a direct RI study on select patient subsets is worth investigation.

Ursolic Acid Regulates Immune Balance, Modulates Gut Microbial Metabolism, and Improves Liver Health in Mice

Ursolic acid (UA) has demonstrated significant immunomodulatory and hepatoprotective effects; however, the underlying mechanisms remain unclear. This study aims to analyze the impact of UA on the gut microbiome, metabolome, and liver transcriptome, investigate UA’s role in maintaining gut immune homeostasis and liver health, and evaluate the potential contributions of gut microbes and their metabolites to these beneficial effects. Our findings indicate that UA enhances immune balance in the jejunum, fortifies intestinal barrier function, and promotes overall gut health. UA modulates the intestinal microbiota and its metabolic processes, notably increasing the abundance of beneficial bacteria such as Odoribacter and Parabacteroides, along with their metabolites, including ornithine and lactucin. Additionally, UA inhibits the expression of interleukin-1 receptor 1 (IL1R1) and calcium (Ca2+) voltage-gated channel auxiliary subunit beta 2 (CACNB2) while enhancing the synthesis pathways of retinol and ascorbic acid, thereby exerting a protective influence on liver function. In summary, UA enhances intestinal immune homeostasis and promotes liver health, with these advantageous effects potentially mediated by beneficial bacteria (Odoribacter and Parabacteroides) and their metabolites (ornithine and lactucin).

Whether the Liver-to-Portal Vein Ratio is Applicable for Evaluating the European Society of Gastrointestinal and Abdominal Radiology Hepatobiliary Phase in Gd-EOB-DTPA-Enhanced MRI?

This study aimed to verify whether the Liver-to-portal Ratio (LPR) can assess the adequacy of the Hepatobiliary Phase (HBP) for patients with different liver functions. A total of 125 patients were prospectively enrolled in the study and graded into the non-cirrhosis group (45), Child-Pugh A group (40), and Child- Pugh B/C group (40). The LPR on HBP was calculated after eight HBPs were obtained within 5-40 minutes. The adequate HBP was determined according to the 2016 European Society of Gastrointestinal and Abdominal Radiology (ESGAR) consensus statement. The differences in LPR and lesions' conspicuity between 10-min HBP and adequate HBP were analyzed by paired t-test and Wilcoxon signed-rank test, respectively. The chisquare test was used to test the difference in proportion with LPR larger than 1.462 between 10-min HBP and adequate HBP. The differences in LPR and lesions' conspicuity between 10-min HBP and adequate HBP were significant in Child-Pugh A and Child-Pugh B/C groups (P < 0.05), except for the non-cirrhosis group (P > 0.05). The differences in proportion with LPR larger than 1.462 between 10-min HBP and adequate HBP were not statistically significant in all groups (all P > 0.05). The adequate HBP obtained according to the 2016 ESGAR consensus statement could provide larger LPR and better lesions' conspicuity than 10- min HBP, especially for cirrhotic patients; however, the efficacy of using an LPR cutoff of 1.462 as the standard of the adequate HBP may be compromised in patients with cirrhosis.

Investigating the effect of adding silymarin to the standard treatment of naloxone in methadone intoxication; a double-blind clinical trial

Introduction: In cases of methadone intoxication, the drug is mainly processed by the liver, however, its elimination through the kidneys is also crucial. On the other hand, naloxone therapy is a gold standard treatment for opioid intoxication, the addition of other drugs can improve its benefits and reduce side effects. Objectives: This study aimed to assess the effectiveness of adding silymarin to the standard treatment of naloxone in patients with methadone intoxication, to improve patient outcomes and reduce the risk of complications associated with alone naloxone therapy. Patients and Methods: This clinical trial study aimed to investigate the efficacy of silymarin in combination with standard treatment for methadone intoxication patients. The study employed a control group, which received standard treatment with naloxone, and an intervention group, which received both naloxone and silymarin. Liver functional tests (LFTs), kidney functional tests, malondialdehyde (MDA), and ferric-reducing ability of plasma (FRAP) were measured at admission and post-intervention times to compare the outcomes between the two groups. Statistical analyses, including chi-square, independent and paired t tests, Wilcoxon, and Mann-Whitney tests were conducted to identify significant differences between the groups. Results: Results indicated that 32 and 33 patients were included in the naloxone and naloxone + silymarin groups, respectively. The results showed that the changes in kidney functional tests such as blood urea nitrogen (BUN) and creatinine (Cr), MDA, and FRAP were not statistically significant between the two groups. However, the changes in LFTs, including, aspartate transaminase (AST), alanine transaminase (ALT), and alkaline phosphatase (ALP), were statistically significant. Notably, the LFT changes were more pronounced in the group receiving both naloxone and silymarin, indicating a greater reduction in liver enzymes in this combined treatment group. Conclusion: The addition of silymarin to standard naloxone treatment for methadone intoxication patients could improve liver function, as the combined therapy showed a more pronounced reduction in liver enzyme levels compared to standard treatment alone; however, this combination treatment could not change the kidney function and oxidative stress markers. Trial Registration: The trial protocol was approved by the Iranian Registry of Clinical Trials (identifier: IRCT20210216050377N1; ethical code from Shahrekord University of Medical Sciences; IR.SKUMS.REC.1400.048). This study was also registered in Research Registry website with Unique Identifying Number (UIN) of researchregistry10395.

Sinusoidal communication in chronic liver disease.

The liver sinusoid, mainly composed of liver sinusoidal endothelial cells, hepatic macrophages and hepatic stellate cells, shapes the hepatic vasculature and is key maintaining liver homeostasis and function. During chronic liver disease (CLD), the function of sinusoidal cells is impaired, being directly involved in the progression of liver fibrosis, cirrhosis, and main clinical complications including portal hypertension and hepatocellular carcinoma. In addition to their roles in liver diseases pathobiology, sinusoidal cells' paracrine communication or cross-talk is being studied as a mechanism of disease but also as a remarkable target for treatment. The aim of this review is to gather current knowledge of intercellular signalling in the hepatic sinusoid during the progression of liver disease. We summarise studies developed in pre-clinical models of CLD, specially emphasizing those pathways characterized in human-based clinically relevant models. Finally, we describe pharmacological treatments targeting sinusoidal communication as promising options to treat CLD and its clinical complications.