Serum Alanine Aminotransferase Levels Research Articles

Osimertinib exacerbates immune checkpoint inhibitor-related severe adverse events by activating the IL-6/JAK/STAT3 pathway in macrophages.

The combination of epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and immune checkpoint inhibitors (ICIs) leads to an increased incidence of severe immune-related adverse events (irAEs). However, the mechanisms underlying macrophages in irAEs have not been elucidated. An osimertinib and ICI-induced irAE mouse model was constructed. Lung micro-CT scans were used to assess the degree of inflammatory infiltration. Hematoxylin-eosin staining was used to analyze the histopathologic inflammatory infiltration in mouse liver and lung tissues. Flow cytometry was used to detect the percentages of T cells, NK cells, and macrophages and the expression of EGFR. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum interleukin (IL)-6, alanine transaminase (ALT), ferritin, and tumor necrosis factor (TNF)-α levels. Total RNA extracted from mouse liver macrophages was analyzed by RNA-seq. Simple Western blot analysis was used to detect the IL-6/JAK/STAT3 pathway activation state. Osimertinib combined with ICIs upregulated EGFR expression on macrophages with increased serum IL-6, ALT, and ferritin levels. RNA-seq and simple Western blot analysis of mouse liver macrophages confirmed that that the IL-6/JAK/STAT3 pathway was activated in the combination treatment group. Ruxolitinib blocked the IL-6/JAK/STAT3 pathway and significantly decreased the serum IL-6, ALT, and ferritin levels in the combination treatment group. An osimertinib and ICI-induced irAE mouse model was constructed that showed osimertinib combined with ICIs inhibited EGFR phosphorylation and activated the IL-6/JAK/STAT3 signaling pathway in mouse liver macrophages, which led to the release of relevant cytokines.

Characterization of tea polysaccharides from Tieguanyin oolong tea and their hepatoprotective effects via AMP-activated protein kinase-mediated signaling pathways.

In the present study, we succeeded in extracting tea polysaccharide (TPS) from Tieguanyin oolong tea, and the TPS was characterized. TPS is an acidic heteropolysaccharide containing rhamnose, arabinose, galactose, glucose (Glc), xylose, mannose, galacturonic acid, and guluronic acid. We found that TPS supplementation partially reversed the elevated levels of serum alanine aminotransferase, total cholesterol, and low-density lipoprotein cholesterol in high-fat diet (HD)-induced nonalcoholic fatty liver disease (NAFLD) mice (p<0.05), and hepatic steatosis and impaired Glc tolerance were also ameliorated. After HD intervention, the activity of Adenosine 5'-monophosphate-activated protein kinase (AMPK) and its downstream genes, including Sirtuin 1 (SIRT1), sterol regulatory element-binding protein-1c (SREBP1c), acetyl-coenzyme A carboxylase 1 (ACC1), and adipose triglyceride lipase (ATGL), was significantly inhibited (p<0.05). TPS can increase the expression of these genes. The hepatoprotective effects of TPS in AMPK-/- mice almost completely disappeared. Moreover, the expression levels of SIRT1, SREBP1c, ACC1, and ATGL did not significantly change after TPS supplementation (p>0.05). Therefore, our findings suggest that TPS protects the liver from hepatic glucolipid metabolism disorders in HD-induced NAFLD mice by activating AMPK-mediated signaling pathways.

A006: Liver Function and Risk of Non-Alcoholic Fatty Liver Disease in Patients with Sarcopenia

Background/Aim: Nonalcoholic fatty liver disease (NAFLD) has become increasingly prevalent as one of the most common chronic liver diseases worldwide. Sarcopenia, defined by the decline in muscle mass, power, strength, and performance, has been linked to NAFLD in recent epidemiological research, although findings have been inconclusive. This meta-analysis aimed to consolidate and determine the impact of sarcopenia on liver function, as well as the occurrence and severity of NAFLD in individuals with sarcopenia. Methods: A comprehensive search was conducted in databases including PubMed, Medline, Embase, Scopus, the Cochrane Library, and the Web of Science were searched up to November 20, 2023. Relevant data from the identified articles were extracted and subjected to quality and risk of bias assessment. Meta-analysis was performed utilizing random-effect models. Results: Twenty-two articles were utilized for the analysis. Individuals with sarcopenia exhibited elevated levels of serum alanine aminotransferase (ALT) (SMD = 0.131, 95% CI: 0.039-0.224) and serum aspartate aminotransferase (AST) (SMD = 0.083, 95% CI: 0.043-0.124) compared to healthy control groups. Furthermore, a significantly increased risk of NAFLD (OR=1.538; 95% CI: 1.355-1.744) and notable fibrosis related to NAFLD (OR=1.611; 95% CI: 1.406-1.846) was observed in sarcopenia patients. Conclusion/Discussion: The serum levels of both ALT and AST were found to be elevated in individuals with sarcopenia compared to those in the normal population. Additionally, sarcopenia patients had a higher risk of developing NAFLD, and NAFLD-associated significant fibrosis. In contrast to earlier research, this study incorporated the most recent findings and was the first to investigate potential differences in serum ALT and AST level between sarcopenia patients and healthy control groups. The remaining results aligned with previous studies. These findings emphasize the significance of routine monitoring of liver function in patients with sarcopenia and highlight the need for longitudinal studies to investigate the potential causal relationship between sarcopenia and NAFLD.

Cordycepin improves liver fibrosis and the intestinal flora disturbance induced by 3,5-diethoxycarbonyl-1,4-dihydroxylidine in mice.

Studies have shown that improving the intestinal flora can alleviate the progression of liver fibrosis. Cordycepin has shown potential anti-inflammatory and anti-fibrosis effects. In this study, we aimed to investigate the effects of cordycepin on liver fibrosis and how it affects the intestinal flora composition to determine a potentially effective therapeutic approach for liver fibrosis. C57BL/6 mice were fed a special diet containing 3,5-diethoxycarbonyl-1,4-dihydroxylidine (DDC) to induce liver fibrosis. The histopathological changes in liver tissue and intestinal mucosa were determining via immunohistochemical staining. Serum transaminase levels were determined using biochemical test kits. Faecalibaculum samples were sequenced via 16S rRNA sequencing. Cordycepin reduced DDC-induced liver collagen deposition, improved serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and reduced the levels of endothelial dysfunction markers vascular cell adhesion molecule 1 (VCAM) and thrombomodulin (TM). Our analysis of the intestinal flora composition showed that Dubosiella, Faecalibaculum, and Bifidobacterium were significantly increased in the cordycepin-treated group (P < 0.05). The Dubosiella level was significantly negatively correlated with TM and VCAM levels, and serum levels of ALT and AST (P < 0.05). After treatment with cordycepin, the microvilli length in the intestinal mucosa, the density of goblet cells, and the expressions of occludin and zonula occludens protein 1 (ZO-1) were significantly increased (P < 0.05). We discovered that cordycepin improves liver fibrosis in vivo. We found that Dubosiella levels were considerably increased in the cordycepin-treated group and were significantly negatively correlated with liver sinusoidal endothelial damage.

Vitamin E improves serum markers and histology in adults with metabolic dysfunction-associated steatotic liver disease: Systematic review and meta-analysis.

Multiple clinical trials have been conducted to study the potential benefits of vitamin E for the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD). Despite available evidence, vitamin E is not widely used. This study aimed to assess the effect of vitamin E on serum markers of liver inflammation, specifically serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and histology, including resolution of metabolic dysfunction-associated steatohepatitis (MASH), in adult patients with MASLD. A systematic literature search on randomized controlled trials published in English was conducted using electronic databases. Standardized mean difference (SMD) and mean difference (MD)were used for continuous outcomes, while risk ratio (RR) was used for dichotomous outcomes, with corresponding 95% confidence interval (CI). A total of eight studies were included in the qualitative synthesis while seven studies were included in the meta-analysis. Vitamin E significantly reduced serum ALT and AST levels with SMD of -0.82 (95% CI, -1.13 to -0.51) and -0.68 (95% CI, -0.94 to -0.41), respectively. Vitamin E significantly reduced steatosis, lobular inflammation, and hepatocyte ballooning with a MD of -0.60 (95% CI, -0.83 to -0.37), -0.34 (95% CI, -0.53 to -0.16), -0.32 (95% CI, -0.53 to -0.12), and increased MASH resolution with a RR of 1.9 (95%CI, 1.20 to 3.02). However, vitamin E did not reduce fibrosis, with a MD of -0.23 (95% CI, -0.51 to 0.05). Vitamin E resulted in significant improvement in serum markers of liver inflammation and histology in patients with MASLD.

Hypoglycaemic, anti-hyperlipidemic, and anti-inflammatory activities of Asparagus africanus (Asparaceae) extract on high-fat diet/streptozotocin-induced diabetes in Wistar rats

Objective: To investigate the toxicity and effect of the extract on some complications of diabetes in Wistar rats. Methods: Type 2 diabetes was induced by a combination of a high-fat diet and streptozotocin (35 mg/kg, i.p.). Aqueous extract of Asparagus africanus (EAA) was prepared and administered (p.o.) for 28 d to groups of diabetic rats as well as to groups of normal rats for toxicity. Fasting blood glucose levels, inflammatory cytokines, and lipid profiles were assessed in diabetic rats. Body and organ weight as well as liver and kidney functions were examined to assess the sub-acute toxicity. Results: EAA for 28 d did not affect the body weight, the weight of the liver, kidney, and heart as well as the serum level of aspartate aminotransferase, alanine aminotransferase, urea, uric acid and creatinine in normal rats. In diabetic rats, the administration of EAA significantly lowered hyperglycemia, reduced interleukin (IL)-6, IL-1β, and tumour necrosis factor-α levels, and increased the level of IL-10. EAA also lowered cholesterol, triglyceride, and low-density lipoprotein cholesterol levels and augmented high-density lipoprotein cholesterol in the serum. As a result of the anti-lipidemic effect, EAA reduced the atherogenic index, Castelli indices, and atherogenic coefficient in diabetic rats. EAA showed the presence of flavonoids, alkaloids, tannins, saponins, terpenes, and steroids. Conclusions: The findings of this study demonstrated that EAA is safe. It has the potential to reduce the glucose level and the risk of inflammation and atherogenesis in diabetic patients.

A170: Effects of Exercise on Liver Function and Inflammatory Markers in NAFLD Patients

Background/Purpose: Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition globally, often linked to sedentary behaviors and central obesity. It is characterized by the activation of multiple signaling cascades leading to inflammation, which plays a critical role in the occurrence and progression of NAFLD liver damage. With the absence of targeted pharmacological treatments, lifestyle and dietary adjustments remain primary interventions for many patients. However, the optimal exercise intensity for managing NAFLD remains unclear, with conflicting evidence on its effectiveness in modulating inflammation. This study aimed to clarify the impact of different exercise types and intensities on liver function and inflammation in NAFLD patients. Methods: Using keywords such as “exercise,” “NAFLD,” and “inflammation,” we searched related studies published in the PubMed, Embase, Cochrane Library, and Web of Science databases. Inclusion criteria were randomized controlled trials (RCTs) with an exercise intervention lasting over four weeks, involving NAFLD or NASH patients (≥18 years) diagnosed through clinical, laboratory, and biopsy data, with a focus on liver enzymes and inflammatory markers as outcomes. Results: Twelve RCTs encompassing 543 NAFLD patients were included. Exercise interventions ranged from 12 weeks to 8.6 months, with frequencies of 2 to 5 times weekly and durations of 30 to 90 minutes per session. Overall, the results of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels following aerobic and resistance training were significantly affected (all P &lt; 0.05). However, high-intensity interval training and combined aerobic-resistance exercise showed negligible effects on ALT and AST levels (all P &gt; 0.05). Regarding the effect of exercise on inflammatory factors, exercise training reduced IL-6 levels in six trials (P &lt; 0.05). However, no specific exercise type was found to reduce IL-6 levels. Exercise training had no significant effect on reducing TNF-Α levels, and no specific exercise reduced TNF-Α levels across five trials. Conclusion/Discussion: Exercise, particularly aerobic and resistance training, positively affected liver function in NAFLD patients by reducing liver enzymes and IL-6 levels. Despite these promising findings, the analysis faces limitations, including the heterogeneity of IL-6 and TNF-Α outcomes and insufficient RCTs for high-intensity interval training subgroups. Further research is essential to explore the specific connections between exercise, inflammation, and NAFLD progression.

Relationship between macronutrients and energy intake and liver serum transaminase levels in elderly athletes and non-athletes: findings from the Neyshabur longitudinal study on aging

BackgroundAssessing liver health and its determinants in the elderly is crucial. Lifestyle factors, including nutrition and exercise, may influence liver function. This study aimed to investigate the association between macronutrients and energy intake with serum levels of aminotransferases in elderly Iranian athletes and non-athletes.MethodsA cross-sectional study involving 811 elderly participants (369 athletes, 442 non-athletes) from the Neyshabur Longitudinal Study on Aging (NeLSA) was conducted. Dietary intake was assessed using a food frequency questionnaire. Serum Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were measured. Regression analyses were employed to evaluate the associations between macronutrient intake and liver enzymes, adjusting for potential confounding variables.ResultsIn elderly athletes, higher calorie, protein, and carbohydrate intake were significantly associated with elevated ALT levels (p < 0.01 for all). Additionally, higher carbohydrate and calorie intake were linked to increased AST levels in athletes (p < 0.05 for both). For elderly non-athletes, only higher protein intake was significantly associated with increased ALT levels (p < 0.05), while no nutritional factors were associated with changes in AST levels.ConclusionsThis study revealed that higher calorie, protein, and carbohydrate intake were associated with elevated ALT and AST levels in elderly individuals, particularly athletes. For athletes, all three nutrients were linked to elevated ALT, while only carbohydrates and calories impacted AST. For non-athletes, only protein affected ALT. These findings suggest that tailored nutritional strategies may be necessary to preserve liver health in active aging populations.

Synergistic Protection of Vitamin B Complex and Alpha-Lipoic Acid Against Hepatic Ischemia-Reperfusion Injury: Boosting Antioxidant Defenses in Rats.

This study aimed to investigate the protective effects of vitamin B complex and alpha-lipoic acid (ALA) pre-treatments on hepatic ischemia-reperfusion injury (IRI) in rats, focusing on their potential to enhance antioxidant defense mechanisms and reduce post-ischemic liver damage. Thirty male Wistar albino rats were divided into four groups: sham group (n = 10), IRI group (n = 10), vitamin B group (n = 10), vitamin B + ALA group (n = 10). In the IRI, vitamin B, and vitamin B + ALA groups, the rats underwent 45 min of hepatic ischemia followed by 60 min of reperfusion. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), urea, creatinine, and lactate dehydrogenase (LDH) were measured. Additionally, serum total antioxidant status (TAS) and total oxidant status (TOS) were assessed, and the oxidative stress index (OSI) was calculated. Liver tissue samples were collected for morphological evaluation. In the vitamin B and vitamin B + ALA groups, ALT, AST, urea, creatinine and LDH levels were better compared with the IRI group but the difference was statistically significant for only LDH levels in the vitamin B group and ALT, urea, and LDH levels in the vitamin B + ALA group (p < 0.05). The lowest TOS and OSI levels were reported in the vitamin B and vitamin B + ALA groups and these groups had statistically significantly higher TAS compared with the sham and IRI groups (p < 0.05). Our findings suggest that a vitamin B complex alone or a vitamin B complex + ALA combination reduces post-ischemic hepatic injury by enhancing the anti-oxidative status. The low dose of ALA may be a co-factor in these results and studies with larger doses of ALA are required to determine its effects on IRI of the liver.

Associations between serum levels of liver function biomarkers and all-cause and cause-specific mortality: a prospective cohort study

BackgroundThe liver plays critical roles in human health. Circulating level of liver function biomarkers may associate with the long-term and short-term mortality in general population.MethodsWe used data from US National Health and Nutrition Examination Survey 1988–94 and 1999–2014. People aged ≥ 20 years with measured serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), alkaline phosphatase (ALP), total bilirubin (TB), and albumin (ALB) at baseline were included. All-cause and cause-specific mortality was identified from the National Death Index through 31 December 2015. Additive Cox regression models were applied to assess the correlation patterns between the serum level of these analytes and mortality risk.ResultsA total of 44,508 participants were included; among them, 9,721 deaths occurred during a mean follow-up of 12.5 years. A “J-shaped” correlation was found between serum levels of ALT, AST, and TB and all-cause mortality. The risk of mortality monotonically increased with increasing GGT and ALP levels when their levels exceeded the valley points. A “L-shaped” correlation was found between the serum level of ALB and all-cause mortality. The correlation patterns were comparable among deaths from different causes and were consistent in subgroup and sensitivity analyses. While the integration of all six liver function biomarkers did not yield an optimal predictive performance for mortality (area under ROC curve = 0.706), it demonstrated a significantly better performance compared to any single biomarker..ConclusionCirculating liver function biomarkers showed diverse nonlinear correlations with mortality and may be utilized as part of a screening process to help identify individuals who may be at elevated risk of mortality.

Effects of kelp meal (Laminaria japonica) on the growth, nutrition, and intestinal health of the largemouth bass (Micropterus salmoides)

Macroalgae are both highly productive and rich in bioactive molecules that have been shown to enhance growth and health of fish. Feed with high starch levels affects the health of fish. This study was conducted to investigate the effects of replacing partial starch with kelp (Laminaria japonica) meal (KM) on the growth performance, nutrient composition, and intestinal microbiota of largemouth bass (Micropterus salmoides, LMB). LMB (initial weight 13.00 ± 0.02 g) were fed three diets containing 0 % (K0), 5 % (K5), and 9 % (K9) kelp meal for 8 weeks. The results showed that with the addition of KM, growth performance and feed intake increased significantly, while hepatosomatic index decreased significantly. The whole body and muscle crude protein contents were significantly increased with the addition of KM. Liver catalase activity was significantly increased in K9, while serum malondialdehyde levels declined accordingly. Serum triglyceride, aspartate aminotransferase and alanine aminotransferase levels were significantly lower in K5 than in K0, suggesting that the addition of KM contributed to healthy liver function. The addition of KM to the diet significantly improved intestinal histology and amylase activity. In addition, the Chao index of the intestinal microbiome in the K5 group was significantly higher than in the K0 group. The relevant abundance of beneficial bacteria (Cetobacterium) tended to increase and that of pathogenic bacteria (Plesiomonas) tended to decrease with the addition of KM. In conclusion, partial replacement of starch with kelp meal increased growth performance, feed intake, muscle protein content, the antioxidant capacity and improved intestinal structure, as well as healthy intestinal microbiome. Kelp meal may be a beneficial substitute for starch for healthy aquaculture of M. salmoides.

Effects of Spent Substrate of Oyster Mushroom (Pleurotus ostreatus) on Feed Utilization and Liver Serum Indices of Hu Sheep from the Perspective of Duodenal Microorganisms.

This study aimed to evaluate the effects of Pleurotus ostreatus spent mushroom substrate (P.SMS), which is characterized by high production but low utilization, on feed utilization and liver serum indices from the perspective of duodenal microorganisms. Forty-five 3-month-old Hu sheep were randomly assigned to five groups and fed diets in which whole-plant corn silage (WPCS) was substituted with P.SMS at levels of 0% (Con), 5% (PSMS5), 10% (PSMS10), 15% (PSMS15), or 20% (PSMS20). The results indicated that the addition of P.SMS complexly influenced the apparent digestibility of dry matter, organic matter, and crude protein, with PSMS10 showing the highest digestibility of these nutrients. P.SMS inclusion significantly affected serum alanine aminotransferase levels, with PSMS5 showing higher levels than both the Con and PSMS20 groups (p < 0.05). Importantly, the inclusion of P.SMS did not affect the richness and diversity of duodenal microorganisms. Significant differences in the phyla Verrucomicrobiota and Spirochaetota were observed between the Con and PSMS20 groups. The observed trend towards an increase in the genus Trichoderma (p = 0.057) suggests that P.SMS is susceptible to contamination by this genus, which in turn affects the structure of the intestinal flora. Furthermore, functional gene predictions indicated differences in amino acid metabolism among the groups (p < 0.05). In conclusion, feeding with 10% P.SMS resulted in the highest digestibility without adversely affecting the structure of the duodenal community or liver function.

Huazhi Rougan Granule Alleviates Liver and Intestinal Damage in Non-Alcoholic Fatty Liver Disease by Regulating miR-122 Expression and TLR4/MyD88/NF-κB Pathway Activation.

miR-122 is upregulated in non-alcoholic fatty liver disease (NAFLD) liver tissue, and knockdown of miR-122 protects hepatocytes from lipid metabolism disorders. This study aimed to investigate whether Huazhi Rougan Granule (HRG) alleviates NAFLD liver and intestinal injury by regulating the miR-122-mediated TLR4/MyD88/NF-κB pathway. Rats with NAFLD were constructed by high-fat feeding. Serum levels of total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were measured using a fully automated biochemical instrument. Histopathological changes in the liver and small intestine were observed by HE staining. QRT-PCR detected the expression level of miR-122 in the liver tissues. The protein expression of TLR4, MyD88, NF- κB p65, and p-p65 in liver tissues was detected by western blotting. HRG slowed down the weight gain of NAFLD rats, decreased (P<0.05) the levels of TC, TG, ALT, AST, TNF-α, IL-1β, IL-6, LPS, and Hpt, improved the pathological status of liver and small intestine tissues, upregulated (P<0.05) the expression of ZO-1 and Occludin, downregulated (P<0.05) the protein expression of TLR4, MyD88, and p-p65, and inhibited (P<0.05) the expression of miR-122. HRG may alleviate hepatic and intestinal injuries in rats with NAFLD by regulating the miR-122-mediated TLR4/MyD88/NF-κB pathway.

Tat-Beclin-1 Peptide Ameliorates Metabolic Dysfunction-Associated Steatotic Liver Disease by Enhancing Hepatic Autophagy.

Autophagy plays a crucial role in hepatic lipid metabolism, making it a key therapeutic target for addressing metabolic dysfunction-associated steatotic liver disease (MASLD). This study evaluates the efficacy of the Tat-Beclin-1 (TB-1) peptide, a specific autophagy inducer, in mitigating MASLD. Initially, we examined the impact of the TB-1 peptide on autophagic activity and intracellular lipid metabolism in HepG2 cells treated with oleic acid, using a Tat scrambled (TS) control peptide for comparison. Subsequently, we established a MASLD mouse model by feeding a high-fat diet (HFD) for 16 weeks, followed by intraperitoneal administration of TB-1 or TS. Assessments included liver histopathology, serum biochemistry, and autophagy marker analysis. Our findings indicate that the TB-1 peptide significantly increased the LC3II/β-actin ratio in a dose- and time-dependent manner while promoting the expression of key autophagy markers Beclin-1 and ATG5-12. Furthermore, TB-1 treatment led to a marked reduction in both the size and number of lipid droplets in HepG2 cells. In vivo, HFD-fed mice exhibited increased liver weight, elevated serum alanine aminotransferase levels, and impaired oral glucose tolerance. TB-1 administration effectively mitigated these hepatic and metabolic disturbances. Histological analysis further revealed a substantial reduction in the severity of hepatic steatosis and fibrosis in TB-1-treated mice compared to TS controls. In conclusion, the TB-1 peptide shows significant potential in reducing the severity of MASLD in both HepG2 cell models and HFD-induced MASLD mouse models. Enhancing autophagy through TB-1 represents a promising therapeutic strategy for treating MASLD.

Kakuol and asarinin protecting liver injury via HSP90AA1/CDK2/mTOR signaling pathway

Drug-induced liver injury caused acute hepatic failure and hepatitis frequently. In this investigation, kakuol and asarinin reduced the levels of serum alanine transaminase (ALT), aspartate transaminase (AST) and malondialdehyde (MDA) dramatically, and ameliorated the pathological damage of liver tissues in APAP-induced mice. Furthermore, both compounds increased the viabilities of APAP-induced L-O2 cells and extracellular glutathione (GSH) levels accompanied significantly by reducing the level of intracellular ROS in vitro. In addition, HSP90AA1/CDK2/mTOR signaling pathway and five target proteins (CDK2, HSP90AA1, HRAS, MMP1, mTOR) were proposed from network pharmacology and molecular docking prediction, and then the up-regulation of protein expression of CDK2, mTOR and down-regulation of HSP90AA1, HRAS, MMP1 by kakuol and asarinin in western blotting supported their mechanism.

The Impact of a Ketogenic Diet on Late-Stage Pancreatic Carcinogenesis in Mice: Efficacy and Safety Studies.

High-fat diets (HFDs) have been associated with an increased risk of pancreatic cancer. In contrast, ketogenic diets (KDs) have been shown to display anti-tumor characteristics. The objective of this work was to evaluate the efficacy of a KD on late-stage pancreatic carcinogenesis in a genetically modified mouse model of pancreatic cancer [LSL-KrasG12D/+; Ptf1-Cre (KC) mice], as well as its liver safety, and to compare it to that of an HFD. Six-month-old female and male KC mice were randomly allocated to either a control diet (CD) (%kcal: 20% fat, 15% protein, 65% carbohydrates), an HFD (%kcal: 40% fat, 15% protein, 45% carbohydrate) or a KD (%kcal: 84% fat, 15% protein, 1% carbohydrate) and fed these diets for 6 months. HFD-fed, but not KD-fed, mice showed a 15% increase in body weight, plus elevated serum insulin (2.4-fold increase) and leptin (2.9-fold increase) levels, compared to CD-fed mice. At the pancreas level, no differences in pancreatic cancer incidence rates were observed among the diet groups. Regarding the liver safety profile, the HFD-fed mice had higher serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP), when compared to the CD and KD groups. In addition, upon histologic examination, an HFD, but not a KD, showed a ~2-fold increase in both macro- and microsteatosis, as well as 35% and 32% higher levels of TLR4 and NF-κB activation, respectively, compared to CD-fed mice. In summary, although a KD intervention alone did not prevent pancreatic carcinogenesis, our data suggests that a KD modulates insulin signaling and hepatic lipid metabolism, highlighting its beneficial effects on healthspan and liver function when compared to an HFD.

Assessment of the nutritional impact of substituting fishmeal with enzymatically hydrolyzed jojoba meal (Simmondsia chinensis) in the diets of Nile tilapia, Oreochromis niloticus

Enzymatic hydrolysis is a technology that is widely used to enhance the biological and functional characteristics of plant proteins and deactivate anti-nutritious components. In order to tackle this pressing issue, considerable research has been conducted on plant-based proteins as a potential substitute. This study sought to comprehensively examine the impacts of replacing fish meal with enzymatically hydrolyzed jojoba meal (EHJM) in the Nile tilapia, Oreochromis niloticus diets. After the enzymatic hydrolysis process for jojoba meal, hydrolyzed amino acid content increased in enzymatically hydrolyzed jojoba meal (EHJM), while fiber content, phytic acid, saponins, and trypsin inhibitors dramatically decreased. A thorough evaluation of key parameters included growth, gene expression, digestive enzyme activity, digestibility, intestinal histomorphometry, biochemical indicators, and antioxidant enzyme activity. Fish (n = 360, 6.41 ± 0.05 g fish−1) were allocated at random to four groups consisting of four replacement levels of fishmeal protein content with EHJM: 0 % (control diet), 25 % (EHJM25), 50 % (EHJM50) and 75 % (EHJM75) for 74 days. The results showed both the control diet and the EHJM25 groups showed remarkable improvements in performance metrics such as final body weight, specific growth rate, weight gain, feed conversion ratio, and protein efficiency ratio, with no discernible variations between them. The inclusion of EHJM up to 50 % produced a noteworthy (P < 0.05) rise in the intestinal lipase and amylase activities. Furthermore, a high apparent digestibility coefficient for crude lipid and protein values was observed in EHJM25% and EHJM50%. The presence of EHJM up to 25 % in tilapia diets, as a substitute for FM, had a significant impact (P < 0.05) on various parameters in the intestine, including goblet cells, muscularis mucosa, villi height, villi width, absorption area, and height muscularis. Moreover, the inclusion of EHJM with different levels in tilapia diets resulted in a noticeable reduction (P < 0.05) in alkaline phosphatase (ALP) and serum alanine aminotransferase (ALT) levels, with fish given the EHJM75% diet showing the lowest amounts in their plasma. In addition, the amount of plasma total protein, albumin, and globulin were found to rise sharply with the escalating replacement of EHJM in fish diet, reaching the highest values in the EHJM25% and EHJM50% diets. Interestingly, the catalase (CAT) and superoxide dismutase (SOD) levels in fish that were given the control diet and EHJM25% showed a remarkable increase compared to the other treatments (P < 0.05). Fish fed EHJM50% diet had the highest glutathione peroxidase and the lowest malondialdehyde levels. In addition, the fish that were fed the control diet exhibited the highest expression of insulin-like growth factor and growth hormone genes, compared to those fed the EHJM25% diet. Based on the results, the EHJM25% and EHJM50% diets were more effective than the EHJM75% diet in improving the efficiency of Nile tilapia. The inclusion of EHJM in Nile tilapia diets had a neutral effect on growth indices compared to a fishmeal diet (control diet). The optimal replacement level is 55.3 %.

The Protective Effects of Mito-TEMPO on Acetaminophen-induced Hepatotoxicity: A Systematic Review

Background: Acetaminophen overdose is a leading cause of acute liver failure glob-ally. Current treatment options, primarily N-acetylcysteine (NAC), have limitations. Mito-TEMPO (Mito-T), a mitochondria-targeted antioxidant, has shown potential in preclinical stud-ies. This systematic review evaluated the evidence for Mito-T's hepatoprotective effects against acetaminophen-induced liver injury. Methods: We conducted a comprehensive search of databases and grey literature following PRISMA guidelines. Studies published between 2000 and 2023 on Mito-T and acetaminophen-induced hepatotoxicity in animal models were included. Data on study characteristics, inter-ventions, outcomes, and risk of bias were extracted. Results: Six high-quality studies were included. Mito-T administration significantly reduced serum alanine transaminase (ALT) levels, a marker of liver injury, compared to controls. Mito-T also protects against hepatocellular necrosis, apoptosis, and mitochondrial dysfunction. These effects were likely mediated by Mito-T's ability to scavenge reactive oxygen and nitrogen spe-cies within mitochondria. Conclusion: This review provides strong evidence that Mito-T effectively protects against ac-etaminophen-induced liver injury in animal models. Mito-T’s mechanisms of action address a critical pathophysiological pathway in acetaminophen toxicity. While limitations, including the use of animal models and potential for publication bias, exist, the findings suggest Mito-T holds promise as a novel therapeutic option. Further studies are needed to assess Mito-T's safety, pharmacokinetics, and optimal dosing in humans. Clinical trials comparing Mito-T against NAC are warranted if toxicity profiles are favorable. Additionally, investigating Mito-T's po-tential in other diseases involving oxidative stress is crucial.

Therapeutic Effectiveness of Prunus dulcis for Nephroprotective and Hepatoprotective in Albino Mice

Background: Nephrotoxicity caused by GM is a complicated occurrence that results in a variety of structural and functional changes, including lesions in the glomerular region and proximal tubule damage, which leads to sudden kidney failure. The production of reactive oxygen species (ROS) has also been linked to GM. Acute hepatic impairments caused by medication might lead to rapid deterioration of liver function. Objective: The purpose of this study was to evaluate the suspension of nuts of Prunus dulcis at a lower dose (800 mg/kg, b.w.) and a higher dose (1600 mg/kg, b.w.) for nephroprotective and hepatoprotective activities. Materials and Methods: Drug-induced nephrotoxicity and drug-induced hepatotoxicity models were used to evaluate the nephroprotective and hepatoprotective activity using albino mice. A histopathological study was also performed. Results: Suspension of nuts Prunus dulcis exhibited significant nephroprotective and hepatoprotective activity. Suspension of nuts from Prunus dulcis at a higher dose (1600 mg/kg b.w.) showed higher nephroprotective and hepatoprotective activity compared to the lower dose (800 mg/kg). The nephroprotective activity was evident by decreased serum creatinine, uric acid, serum urea, and BUN, which were confirmed by histological study. The hepatoprotective effect was confirmed by significantly decreased serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total protein, and total bilirubin levels in treated groups, which were further confirmed by histopathological study. Conclusion: The result suggests that Prunus dulcis possesses nephroprotective and hepatoprotective activities.

Ren-Shen-Bu-Qi decoction alleviates exercise fatigue through activating PI3K/AKT/Nrf2 pathway in mice.

Fatigue is a prevalent issue that can lead individuals to a sub-health condition, impacting their work efficiency and quality of life. There are limited effective treatment options available for fatigue. Ren-Shen-Bu-Qi decoction (RSBQD) is a proprietary herbal remedy that is designed to address fatigue. However, the specific pharmacological mechanisms and basis of RSBQD are not yet fully understood. This study aimed to investigate the pharmacological effects and mechanisms of RSBQD in a mouse model of exercise fatigue. UPLC-Q-Orbitrap HRMS was used to analyze the chemical composition of RSBQD. The pharmacological basis and molecular mechanism of RSBQD on exercise fatigue were predicted using network pharmacology analysis. Subsequently, an exercise fatigue mouse model was established and used to analysis the effects of RSBQD. The potential mechanisms were verified by hematoxylin-eosin (HE) staining, real-time fluorescence quantitative PCR (RT-qPCR), Western blot (WB) and molecular docking. The results showed that 88 main components of RSBQD were identified, which have mainly belonged to flavonoids and carboxylic acid compounds. The network pharmacology analysis indicated that RSBQD ameliorate fatigue through PI3K/AKT signaling pathway. Notably, RSBQD prolonged the swimming time and diminished body weight loss of exercise fatigue mice (P < 0.05). Meanwhile, RSBQD significantly alleviated the injury of liver and kidney induced by exhaustive exercise, and decreasing the serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), urea and BUN levels (P < 0.05). In addition, RSBQD was found could relieve exercise fatigue by decreasing the content of creatine kinase (CK), lactate dehydrogenase (LDH), and lactic acid (LA), but increasing the blood glucose (GLU) and liver glycogen (HG) levels (P < 0.05). RSBQD also significantly increased the hepatic superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) but decreased hepatic malondialdehyde (MDA) levels. Moreover, RSBQD was able to upregulate protein level of activated Nrf2 and PI3K/AKT signaling pathways. RSBQD mitigates exercise fatigue by reversing metabolic changes and reducing oxidative damage through the PI3K/AKT/Nrf2 signaling pathway. This study offers pharmacological support for the utilization of RSBQD in exercise fatigue treatment.