Serum Aspartate Aminotransferase Levels Research Articles

Early Escalation to CentriMag for Acute Myocardial Infarction-Induced Out-of-Hospital Cardiac Arrest With Refractory to Extracorporeal Membrane Oxygen Support.

The mortality rate of acute myocardial infarction (AMI)-related refractory cardiogenic shock (rCS) remains high, particularly in patients experiencing cardiac arrest with extracorporeal cardiopulmonary resuscitation (ECPR). This study aimed to evaluate the outcomes of early escalation to CentriMag for AMI-induced out-of-hospital cardiac arrest (OHCA) with ECPR. Patients with AMI-induced OHCA with refractory to ECMO support after ECPR were enrolled. Clinical data were analyzed to identify predictive factors for mortality and survival benefits. Eighty-nine patients were enrolled, of whom 26 underwent CentriMag implantation. The 1-year survival rate for those with the implantation was 34.6%. In contrast, those without implantation showed a survival rate of 7.9%. The average time from the initiation of ECPR to CentriMag implantation was 22.5 ± 14.6 h. The surgical mortality group exhibited a larger body surface area, longer intervals from CPR to ECPR, shorter duration of CentriMag support, and higher preoperative serum creatinine and postoperative day 1 serum aspartate aminotransferase levels. A prolonged interval from CPR to ECPR was identified as an independent risk factor for mortality. Extended duration of CentriMag support was associated with improved survival outcomes. Early CentriMag implantation rescues patients experiencing AMI-related OHCA with rCS and refractory to ECMO support after ECPR. This intervention provides a critical time window, serving as a safe bridge to decision.

Clinical and biochemical characteristics for patients with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes syndrome: a pilot observational study

BackgroundPolyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is rare life-threatening condition associated with a clonal plasma cell neoplasm.ObjectiveThe aim of this study is to investigate the clinical and biochemical features in patients with POEMS syndrome before and post-therapy.MethodsCharacteristics of demographic information, underlying diseases, clinical manifestations, laboratory indicators, and imaging examination were retrospectively collected when diagnosed and post-therapy in the patients POEMS syndrome between 2018 and 2024.ResultsNineteen newly-diagnosed, treatment-naïve patients with POEMS syndrome were enrolled. The diagnosis of POEMS syndrome was re-analyzed and matched the diagnostic criteria updated in 2023. All patients presented the symptoms of polyneuropathy and positive for M-protein. Most patients suffered with hyperpigmentation (n = 18), organomegaly (n = 18), elevated vascular endothelial growth factor (VEGF) (n = 17), extravascular volume overload (n = 15), sclerotic bone lesions (n = 11), and hypothyroidism (n = 10). Serum alanine aminotransferase, aspartate aminotransferase, total bilirubin, total protein, and albumin levels were down-regulated, while uric acid level was up-regulated in patients with POEMS syndrome. Reduced triiodothyronine, thyroxine, free triiodothyronine levels were negatively correlated with urea nitrogen, creatinine, and uric acid levels in patients with POEMS syndrome. VEGF level, which was negatively correlated with Ca2+ level (r = −0.56), was reduced in most patients with POEMS syndrome receiving bortezomib/ixazomib and lenalidomide/thalidomide therapy. Aspartate aminotransferase, total protein, and estimated glomerular filtration rate levels were increased, while creatinine and uric acid levels were reduced post-therapy in patients with POEMS syndrome.ConclusionPatients with POEMS syndrome had impaired liver and renal function, and effective therapy might partly repair the liver and renal dysfunction.

Metformin alleviates doxorubicin-induced hepatic damage by modulating oxidative stress: a molecular, biochemical, and histopathological approach in a rat model.

Doxorubicin (DOX) is one of the most commonly prescribed anti-cancer drugs. However, DOX-induced hepatotoxicity is a dose-limiting side effect. This study aimed to clarify the potential protective effects of metformin on DOX-induced hepatotoxicity in rats. The animals were divided into six groups (n = 6 each): Control Group, DOX group, metformin 200mg/kg group, DOX + metformin 50mg/kg group, DOX + metformin 100mg/kg group, and DOX + metformin 200mg/kg group. Hepatic injury was induced by a single intraperitoneal injection of DOX (20mg/kg). The activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) in serum were determined. Furthermore, the hepatic histopathological changes were evaluated. To identify the markers of oxidative stress, the level of malondialdehyde (MDA) and the activities of antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) in liver tissue were measured. Results showed that DOX provoked a marked elevation in ALT, AST, and ALP serum levels. In addition, oxidative stress was significantly boosted in DOX-treated rats compared to control rats. All these were abolished with the metformin administration. Histological examination also showed that metformin could substantially reduce DOX-induced alterations. The most prominent effect was observed by high-dose metformin.

The Assessment of Serum Cytokeratin 18 and Liver Function Tests in Chronic hepatitis B patients.

Background Chronic hepatitis is a clinical and pathological disorder, some biochemical testes like serum Alanine Amino-transferase (ALT), Aspartate Amino-transferase (AST) and total serum bilirubin (TSB) used to monitoring hepatitis diseases. Albumin levels in serum fall with liver disease progression, representing decreased synthesis. Prothrombin time evaluate the level of converted prothrombin to thrombin and this represent the synthetic function of the liver. In acute on chronic liver Disease non apoptotic pattern of cell death is predominant .It is confirmed by cleaved K18. Cytokeratin 18 was measured by ELISA Objectives: This study aimed to measure the ALT ,AST ,TSB, Albumin ,PT and K18 levels inthe serum of Iraqi patients who were having Liver disease And study the correlation between the variables mentioned above Materials and Methods: The study included approximately One hundred subjects, ages 20 to 60 year, who were split into two groups , Fifty patient with chronic hepatitisB virus,The second group comprises of 50 subjects who look to be in good health and serves as the control group. Results Serum levels of ALT, AST, TSB, PT and albumin displayed a significant increase in chronic hepatitis B virus group compare with control group . Also, the current study revealed non-significant association of liver function tests with different age groups, except total serum Bilirubin values decline significantly with increasing age, and there was a significant gender difference in AST concentration. While, there was non-significant gender difference in further liver parameters. Conclusion Among chronic hepatitis B patientin Babylon province, abnormality of liver function tests in different age and gender groups; indicat the significant linke with the development of chronic hepatitis B virus.

Cordycepin alleviates metabolic dysfunction-associated liver disease by restoring mitochondrial homeostasis and reducing oxidative stress via Parkin-mediated mitophagy.

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) keeps rising with only a few drugs available. The present study aims to investigate the effects and mechanisms of cordycepin on MASLD. Male C57BL/6 mice were induced with a 90-day high-fat diet (HFD) and intraperitoneal administration with streptozotocin to establish MASLD murine model. Then they were randomly divided into the HFD and cordycepin groups (15, 30, 45mg/kg). Cordycepin was orally given for 30days. Serum total cholesterol (TC), triacylglyceride (TG), and aspartate aminotransferase (AST) levels were measured. L02 cells were induced by oleate acid (OA) or lipopolysaccharides (LPS), and treated with cordycepin or combined with inhibitors including chloroquine, 3-Methyladenine, and compound C. Atg7 and Parkin were knocked down in L02 cells using siRNA. Oil Red O and Nile Red staining for measuring lipid deposition. Mitochondria were visualized by transfection with mCherry-TOMM20-N10. Quantitative real-time PCR, Western blotting, and immunofluorescence staining were used to determine expressions of key molecules in inflammation, lipid metabolism, mitochondria homeostasis, and oxidative stress. Cordycepin significantly mitigated lipid deposition and ballooning in the livers of MASLD mice. Serum TC, TG, and AST levels were decreased by cordycepin. Cordycepin alleviated OA-induced lipid deposition and LPS-induced inflammation in L02 cells, attenuated oxidative stress, promoted autophagy, and maintained the autophagic flux by activating AMP-activated protein kinase (AMPK). Cordycepin reduced the accumulation of impaired mitochondria by enhancing Parkin-dependent mitophagy and promoting mitochondrial biogenesis. Cordycepin alleviates MASLD by restoring mitochondrial homeostasis and reducing oxidative stress via activating the Parkin-mediated mitophagy.

Oral administration of Lactobacillus rhamnosus MP108 ameliorates hemolytic jaundice in rats.

Accumulating evidence suggests that specific probiotic strains exert effects on hemolytic jaundice (HJ), and probiotic strains of Lactobacillus rhamnosus exhibit potential beneficial effects against HJ. This study aimed to determine the effects of L. rhamnosus MP108 (MP108) on rats with acetylphenylhydrazine (APH)-induced HJ. One week of oral MP108 administration (16 × 109 CFU/kg·day) significantly reversed the HJ-induced body-weight reduction and normalized serum levels of serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), total superoxide dismutase (T-SOD), glutathione peroxidase (GSH-PX), hydrogen peroxide (H2O2), andsuperoxide anion (O2-) in HJ rats. Furthermore, significant improvements were observed in the pathological changes of liver and intestinal tissues. 16S rRNA high-throughput sequencing of fecal samples demonstrated that MP108 altered gut microbiota composition by increasing Lacticaseibacillus spp. abundance, which correlated with the serum levels of ALT, AST, TBIL, T-SOD, GSH-PX, H2O2, and O2-. In summary, these results provide evidence that MP108 has the potential to improve HJ symptoms by alleviating hepatic impairment, which is associated with changes in gut microbiota composition. PRACTICAL APPLICATION: The study indicates that MP108 can modulate the gut microbiota, improve liver function, and thereby alleviate the symptoms of hemolytic jaundice (HJ). These findings suggest a promising therapeutic approach for HJ, offering potential benefits to patients with related conditions.

Ningxiang pig-derived Lactobacillus reuteri improves the gut health of weaned piglets by regulating intestinal barrier function and cytokine profiles

Weaning stress in piglets can induce intestinal damage, resulting in impaired growth performance. Probiotics have emerged as significant contributors to enhancing gut health in piglets. This study aimed to evaluate the effects of Lactobacillus reuteri (L. reuteri) supplementation on growth performance, intestinal immunity, and intestinal barrier integrity in weaned piglets. In this investigation, fourteen healthy weaned piglets of similar age and weight, were randomly assigned to two groups (n = 7), receiving either normal saline (Control group) or L. reuteri (L-treatment group) over a 16-day period. The findings revealed no significant impact of L. reuteri on growth performance compared to controls. However, it lowered serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels (P < 0.05) and elevated serum concentrations of Immunoglobulin A (IgA), immunoglobulin G (IgG), and secretory immunoglobulin A (sIgA) (P < 0.05). Additionally, L. reuteri notably enhanced the villus height-to-crypt depth ratio in the ileum (P < 0.05) and increased mRNA expression of zonula occludens-1 (ZO-1), Claudin-1, and ZO-1 in ileal tissue (P < 0.05). Furthermore, L. reuteri reduced mRNA expression of pro-inflammatory cytokines interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) (P < 0.05) in the jejunum and colon while enhancing the expression of the anti-inflammatory cytokine interleukin-10 (IL-10) (P < 0.05) in both the ileum and colon. This study demonstrates that L. reuteri isolated from Ningxiang pigs can improve the intestinal health of weaned piglets by modulating gut barrier function and cytokine levels.

Effects of chronic cold stress and thermal stress on growth performance, hepatic apoptosis, oxidative stress, immune response and gut microbiota of juvenile hybrid sturgeon (Acipenser baerii ♀ × A. schrenkii ♂)

The current study was conducted to investigate the effects of chronic cold stress and thermal stress on the growth performance, hepatic oxidative status, immune response, apoptosis and gut microbiota in juvenile hybrid sturgeon. The fish (initial mean weight: 21.4 ± 0.3 g) was reared at three temperatures (14 °C, 22 °C, and 30 °C) for 16 d, which were termed as low temperature group (LT), moderate temperature group (MT), and high temperature group (HT), respectively, and the second group was regarded as control group in this study. Each group was assigned randomly to three tanks with 15 fish per replica. The results indicated that cold stress resulted in a significant reduction of growth metrics and a significant increase of feed conversion ratio in fish compared with MT group. Interestingly, cold stress increased hepatocyte apoptosis revealed by TUNEL staining, along with nuclear disappearance in H&E-stained sections and elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Transcriptional levels of apoptosis-related genes and toll-like receptor signaling pathway components were significantly up-regulated in liver under cold stress. Compared with control group, in terms of thermal stress, the growth performance and feed utilization of fish were declined to some extent compared with MT group. Moreover, high temperature significantly elevated hepatic productions of malondialdehyde and hydrogen peroxide, as well as increased activities of some antioxidant enzymes in liver. In addition, low and high temperature induce changes in the composition of gut microbiota. Overall, the results suggested that cold stress decelerated growth performance, induced hepatocyte apoptosis, and enhanced innate immunity in hybrid sturgeon to cope with additional stressors. Whereas, thermal stress resulted in hepatic oxidative stress in liver and the protective responses in the antioxidant enzymes in fish were activated. These results provided insights into the different physiological adaptation strategies in responsive to cold stress and thermal stress in this cold-water fish.

Experimental model of non-alcoholic fatty liver disease in pregnant rats to evaluate the effectiveness of therapy

Background: The growing incidence of non-alcoholic fatty liver disease in the population contributes to the development of obstetric complications during pregnancy and demands searching effective methods of hepatoprotective therapy. Aim: The aim of this study was to evaluate the efficacy of therapy for non-alcoholic fatty liver disease in an experimental model in pregnant rats. Materials and methods: this experimental study was carried out on 19 female Wistar rats weighing 250–300 g, obtained from the laboratory animal nursery of SMK Stezar Ltd. (Vladimir, Russia). Using a high-fat diet, non-alcoholic fatty liver disease was simulated in the study groups as follows. Group 1 (n = 7) consisted of non-pregnant rats, group 2 comprised pregnant rats without therapy (n = 6), and group 3 included pregnant rats and intraperitoneal administration of 12 mg of the low-molecular sugar preparation from day 16 to day 20 of gestation (n = 6). During the experiment, the body weight of female rats was measured weekly. After the experiment was completed, we evaluated the blood serum levels of aspartate aminotransferase, alanine aminotransferase, ferritin, triglycerides, total cholesterol, total bilirubin, urea, total alkaline phosphatase, bile acids, glucose, C-reactive protein, cholinesterase, and malondialdehyde, as well as catalase activity. Histological examination of the rat liver was carried out using the standard method with hematoxylin and eosin staining. Results: This study showed that high-fat diet caused oxidative stress manifested by decreased the blood catalase level and increased malonovodialdehyde in both pregnant and non-pregnant females; the blood bile acids level also increased. In pregnant rats with non-alcoholic fatty liver disease, the serum C-reactive protein and total alkaline phosphatase levels increased, the cholinesterase level decreased, and the catalase activity decreased even more. In the study group using the low-molecular sugar preparation, biochemical parameters in non-alcoholic fatty liver disease improved, probably due to the effect on lipogenesis and oxidative stress in the liver. The histological pattern was characterized by the impaired structural characteristics of hepatocytes and the circulatory bed. With the use of the low-molecular-weight sugar preparation, we noted a tendency to restore the structure of the hepatic beam area and a decrease in the manifestations of steatosis. Conclusions: The use of the low-molecular-weight sugar preparation in the treatment of non-alcoholic fatty liver disease improves biochemical blood parameters and tends to restore the histological structure of the liver.

One-step engineered mesenchymal stem cell-derived exosomes against hepatic ischemia-reperfusion injury.

Hepatic ischemia-reperfusion injury (IRI) is an important factor affecting the prognosis of patients undergoing surgery. Exosomes derived from mesenchymal stem cells (MSC-EXOs) are widely used and play a therapeutic role in hepatic IRI. However, natural exosomes lack liver-targeting ability and have low bioavailability. In this study, MSC-EXOs were simply modified with OPDEA-PCL or liver-targeting DSPE-PEG2000-Galactose, forming OPDEA-PCL-modified MSC-EXOs (OP-EXOs) or DSPE-PEG2000-Galactose-modified MSC-EXOs (GPEG-EXOs). In mouse hepatic IRI model, OP-EXOs and GPEG-EXOs both significantly reduced alanine aminotransferase (ALT), aspartate aminotransferase (AST), and lactate dehydrogenase (LDH) levels in serum after hepatic IRI, alleviating liver injury. Transcriptomic and proteomic analyses showed that OP-EXOs and GPEG-EXOs reduced hepatic IRI by downregulating the expression of S100A8, S100A9, SELP, and ANXA2 in the liver following IRI. This study opens a new paradigm for the treatment of hepatic IRI using engineered MSC-EXOs with the potential to improve the prognosis of liver surgery.

Ginsenoside Rd protects against acute liver injury by regulating the autophagy NLRP3 inflammasome pathway

Ginsenoside Rd (Rd) is a bioactive compound predominantly found in Panax ginseng C.A. Meyer and Panax notoginseng (Burkill) F.H. Chen ex C.H. Chow, both species belonging to genus Panax in the Araliaceae family. However, its hepatic protective effect against acute liver injury and related mechanistic action remain unexplored. To investigate the protective effect of Rd against thioacetamide (TAA)-induced acute liver injury and assess its underlying regulatory mechanisms related to autophagy and inflammation. Forty-eight 8 weeks old C57BL/6 mice were treated with saline (control or model group), Rd (12.5 mg/kg, 25 mg/kg or 50 mg/kg), and diammonium glycyrrhizinate (DG, 30 mg/kg) for three days. Then the mice were stimulated with TAA to establish acute liver injury model, excluding the control group. HSC-T6 cells were treated with Rd at concentrations of 2.5, 5, or 10 µM, for 12 h with or without Lipopolysaccharide (LPS) stimulation at 100 ng/mL. Immunofluorescence staining, qPCR and Western blot were employed to analyze the expressions of genes and proteins associated with inflammation and autophagy. To validate the role of Rd in regulating autophagy and inflammation, the autophagy inducers, rapamycin and GSK621, were utilised in reverse validation experiments in cells. Rd exhibited significant hepatic protective effects in mice by reducing the serum levels of Aspartate aminotransferase (AST), Alanine aminotransferase (ALT), Glutathione S-transferase (GST) and Lactate dehydrogenase (LDH) with acute liver injury. It exhibited strong anti-inflammatory effect by reducing inflammation associated protein, such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), nod-like receptor protein 3 (NLRP3), associated speck-like protein containing a CARD (ASC), interleukin-18 (IL-18) and interleukin-1β(IL-1β) proteins and the mRNA expression levels of COX-2, Tumor Necrosis Factor α (TNF α), interleukin-6 (IL-6) and iNOS were decreased in liver tissue. And Rd inhibited LPS-induced inflammation by reducing the expression of COX-2 and NLRP3 in HSC-T6 cells. Moreover, not only in vivo but also in vitro, Rd downregulated the expression of LC3II, Beclin1, phosphorylation-AMP-activated protein kinase (p-AMPK), phosphorylation-ULK1 (p-ULK1) and upregulated the expression of p62 and phosphorylation-mechanistic target of rapamycin (p-mTOR) to suppress autophagy via the AMPK/mTOR/ULK1 pathway. Finally, the inhibitory effects of Rd on autophagy and inflammation in HSC-T6 cells were partially blocked by rapamycin and GSK621. Rd is a promising therapeutic agent to protect liver against TAA-induced acute liver injury by regulating the autophagy-NLRP3 inflammasome pathway.

Diagnostic Biochemical Changes Identified in a Cohort of Patients with Coronavirus-19 (COVID-19) Disease

Backgroun: SARS-CoV-2 infection was associated with inflammatory, metabolic, haematological, and immunological changes, which contributed to the increase in morbidity and mortality. Objective: To illustrate changes in some biomarkers (ESR, ferritin, CRP, D. dimer, ALT, AST, creatinine, and urea) during COVID-19 and their predictive value in the diagnosis of SARS-CoV-2 infection, especially in rural and urban areas in which sophisticated tests were not available. Materials and Methods: The study includes 154 COVID-19 patients with positive RT-PCR. Sixty age and sex-matched individuals were included as controls. The study was conducted during the period from 23rd July 2021 to the end of December 2021. The subjects with a history of liver diseases, pregnant women, an age of less than 18, and chronic renal failure were excluded. The informed consent was taken from each individual before their enrolment in the study. The study was performed in compliance with the World Medical Association Declaration of Helsinki. Venous blood samples were collected from both groups and tested for determination of creatinine, urea, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), D dimer, ferritin, and C-reactive protein (CRP) using a Mindray BS 240 chemical auto-analyzer. Results: The mean serum values were significantly higher (P= 0.01 – 0.001) in COVID-19 patients as compared to matched controls for creatinine, blood urea, ALT, AST, ESR, LDH, D- dimer, ferritin, and CRP. In addition, the mean serum levels of ALT, AST, ESR, LDH, D-dimer, ferritin, and CRP were higher than the values of normal ranges. Although, creatinine and urea mean serum values were significantly higher in COVID-19 patients, their mean values were within the normal range values. ESR was highly significantly (p &lt; 0.001) correlated with ALT, AST, LDH, urea, ferritin, and CRP. While LDH was highly significantly correlated with creatinine, urea, ESR, ferritin, and CRP. Also, D. dimer was significantly highly correlated with ferritin, and CRP. Serum ferritin was highly significantly correlated with creatinine, urea, ESR, LDH, D. dimer, and CRP. While CRP was highly significantly correlated with creatinine, urea, ESR, LDH, D. dimer, and ferritin. Conclusion: ESR, CRP, Ferritin, D. dimer, LDH, AST, ALT, urea, and Creatinine levels in venous blood were significantly elevated in COVID-19 patients compared with controls. Sex- influenced serum levels of C-reactive protein, creatinine, and urea in this study cohort. Serum levels of tested biomarkers may be useful in the diagnosis of COVID-19 in primary healthcare centres, especially in rural areas in developing countries.

Probiotic Limosilactobacillus reuteri DSM 17938 Alleviates Acute Liver Injury by Activating the AMPK Signaling via Gut Microbiota-Derived Propionate.

Limosilactobacillus reuteri DSM 17938 (L. reuteri DSM 17938) was one of the most widely used probiotics in humans for gastrointestinal disorders, but few studies have investigated its role in drug-induced liver injury (DILI). Here, we evaluated the efficacy of L. reuteri DSM 17938 using a mouse model of DILI induced by triptolide. Pregavage of L. reuteri DSM 17938 for 1 week remarkably lowered hepatic inflammatory cytokines level and oxidative stress, with diminished serum alanine transaminase and aspartate aminotransferase levels. Metabolomics and RT-qPCR analysis confirmed its ability in ameliorating TP-disrupted hepatic fatty acid β oxidation. Genome annotation of L. reuteri showed its ability to modulate energy metabolism. Targeted metabolomics demonstrated that L. reuteri DSM 17938 modified the short fatty acid profiles in cecum, especially enhancing propionate levels. Further experiments found that L. reuteri DSM 17938 can activate AMPK signaling by upregulating gut microbiota-derived propionate level, thus restoring impaired mitochondrial biogenesis and energy supply processes to recover energy homeostasis, which leads to diminished ROS production and oxidative stress injury in hepatocytes. Besides, AMPK inhibitor dorsomorphin abolished all the effects on propionate protecting mitochondria and energy metabolism. This study established probiotic therapy of L. reuteri DSM 17938 as a preventive intervention for DILI in clinical. We also revealed that L. reuteri DSM 17938 can activate AMPK signaling by propionate, facilitating a deeper understanding of the action mechanism of L. reuteri DSM 17938 against acute liver injury and contributing to the development of its postbiotics and wider applications.

FGF21 and APOA1 mRNA-based therapies for the treatment of experimental acute pancreatitis

BackgroundAcute pancreatitis (AP) presents a significant clinical challenge with limited therapeutic options. The complex etiology and pathophysiology of AP emphasize the need for innovative treatments. This study explores mRNA-based therapies delivering fibroblast growth factor 21 (FGF21) and apolipoprotein A1 (APOA1), alone and in combination, for treating experimental AP.MethodsLiver-targeted lipid nanoparticles (LNP)-mRNA formulations encoding FGF21, APOA1, and a chimeric APOA1-FGF21, were first tested for protein expression and bioavailability in vitro and in mice fed a high-fat diet. Efficacy studies were performed in the caerulein-induced AP (Cer-AP) model, and a new AP model combining ethanol feeding with ethanol binge plus palmitoleic acid administration, the EtOH/POA-AP model. A single dose of the APOA1, FGF21, and APOA1-FGF21 LNP-mRNAs formulations was administered in both models. Serum levels of pancreatic lipase (LIPC), amylase (AMYL), and aspartate aminotransferase (AST), along with pancreatic tissue analyses using two histopathological scores were performed to evaluate treatment effects.ResultsIn vitro studies demonstrated the translation and secretion of APOA1, FGF21, and APOA1-FGF21 proteins encoded by the LNP-mRNAs. In vivo, LNP-mRNA administration increased serum levels of the respective proteins in metabolically impaired (i.e. high fat diet-fed) mice. In the Cer-AP model, serum markers of pancreatic injury were similarly reduced when mice were treated with APOA1, FGF21, and APOA1-FGF21 LNP-mRNA, and this effect was also observed in the histopathological analyses. The EtOH/POA-AP model was more aggressive than the Cer-AP model. FGF21 and APOA1-FGF21 LNP-mRNAs were protective according to LIPC and AMYL serum levels, while APOA1 LNP-mRNA had little effect. On the other hand, histological improvements were more evident in mice receiving APOA1 LNP-mRNA. In the EtOH/POA-AP model, FGF21 and APOA1-FGF21 LNP-mRNAs reduced serum AST levels, indicating hepatoprotective activity.DiscussionThis proof-of-concept study demonstrates the potential of mRNA-based therapies delivering FGF21 and APOA1 in experimental AP. While individual treatments effectively reduced pancreatic injury, the APOA1-FGF21 fusion molecule did not exhibit superior activity. Liver-targeted LNP-mRNA administration may offer a promising approach for treating AP, leveraging endogenous production pathways for therapeutic proteins. Further research is warranted to elucidate the mechanisms underlying their therapeutic efficacy and optimize treatment regimens for clinical translation.

Scopoletin alleviates acetaminophen-induced hepatotoxicity through modulation of NLRP3 inflammasome activation and Nrf2/HMGB1/TLR4/NF-κB signaling pathway.

Scopoleitin (SP), a bioactive compound from many edible plants and fruits, exerts a wide range of biological activities, however the role and mechanism of SP in acetaminophen (APAP)-induced hepatotoxicity remains unclear. In this study, we verified the protective effect of SP on APAP-induced liver injury (AILI) hepatotoxicity and explore the underlying molecular mechanisms. Here, we showed that SP alleviated AILI by reducing serum alanine transaminase (ALT) and aspartate aminotransferase (AST) levels, hepatic histopathological damage, inflammation, and liver cell apoptosis. In addition, SP attenuated the accumulation of malondialdehyde (MDA) and exhaustion of glutathione (GSH) levels and increased the superoxide dismutase (SOD) levels induced by APAP. Consistently, SP significantly reduced the gene transcription of cytochrome P450 (CYP)2E1, CYP1A2, and CYP3A11 in the livers of mice induced by APAP. Moreover, SP pretreatment effectively promoted the expression of Nrf2, Keap1, and its signal downstream HO-1, NQO1, GCLc, and GCLm, suggesting the activation of the Nrf2 signaling pathway. SP inhibited APAP-induced hepatocyte apoptosis by regulating the protein levels of apoptosis-related proteins (cytochrome C, Bax, Caspase-3, Bcl2, and PARP). SP suppressed APAP-induced expression of NLRP3 and reduced the levels of proinflammatory factors, including tumor necrosis factor-alpha (TNF-α), F4/80, Caspase-1, and interleukin (IL)-1 beta (IL-1β). Moreover, SP downregulated APAP-induced high-mobility group box 1 (HMGB1) and toll-like receptor 4 (TLR4) expression, inhibited nuclear factor kappa-B (NF-κB) and MAPK activation. Taken together, our study reveals the protective roles of SP against AILI through the downregulation of NLRP3 expression, and the inhibition of the Nrf2/HMGB1/TLR4/NF-κB signaling pathways.

Timosaponin B II as a novel KEAP1-NRF2 inhibitor to alleviate alcoholic liver disease:Receptor structure-based virtual screening and biological evaluation.

Oxidative stress induced by excess ethanol is an important factor in the progression of alcoholic liver disease (ALD). In recent years, inhibiting Kelch-like ECH-associated protein 1 (KEAP1) to activate the antioxidant regulator Nuclear factor erythroid 2-related factor 2 (NRF2) has been considered an effective strategy for treating oxidative stress-related diseases, but its application in ALD remains insufficiently explored. This study aims to discover high-affinity inhibitors targeting the KEAP1 receptor. We conducted virtual screening of a compound library based on a structure-based pharmacophore model, ultimately identifying the candidate compound Timosaponin B II (TBII). Subsequently, we established ALD models in AML-12 cells and C57BL/6 mice, and evaluated the therapeutic effects and mechanisms of TBII on ALD using methods including Immunofluorescence, Western blotting, RT-qPCR, Biochemical assays, and histological staining. Results indicate that TBII significantly improved ethanol-induced liver injury, inhibited the elevation of serum Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Total Cholesterol (T-CHO), and Triglycerides (TG) levels, and reduced lipid droplet accumulation in liver tissues. Furthermore, TBII treatment enhanced the antioxidant capacity of AML-12 cells and mouse liver, increasing Glutathione (GSH) and Superoxide Dismutase (SOD) levels while reducing Malondialdehyde (MDA) and Reactive Oxygen Species (ROS) levels. Mechanistic studies indicated that TBII inhibited the ethanol-induced increase in KEAP1 and reversed the ethanol-induced changes in NRF2 and its downstream targets. In conclusion, this study suggests that TBII may become a potential therapeutic agent for ALD by modulating the KEAP1-NRF2 pathway to alleviate oxidative stress and lipid metabolism abnormalities.

The Use of Coffee Cherry Pulp Extract as an Alternative to an Antibiotic Growth Promoter in Broiler Diets.

Coffee cherry pulp (CCP) is a by-product of coffee bean production. CCP contains amounts of phenolic compounds that are beneficial for animals. This study evaluated the impact of coffee cherry pulp extract (CCPE) supplementation on growth performance, meat quality, carcass characteristics, serum biochemistry, cecum microbial population, intestinal morphology, and immune and antioxidant responses of broilers. Five hundred 1-day-old Ross 308 chicks were randomly assigned to five groups: a basal diet control, a basal diet with antibiotic growth promoters at 0.25 g/kg, and groups supplemented with CCPE at 0.5, 1.0, and 2.0 g/kg diet over 35 days. The results showed that throughout the experimental period, the groups supplemented with CCPE improved their final weight, average daily gain, and feed conversion ratio (p < 0.05). CCPE at 1.0 and 2.0 g/kg diet reduced the average daily feed intake (p < 0.05). In addition, CCPE at 0.5 g/kg reduced levels of serum alanine transaminase and aspartate aminotransferase (p < 0.05). Triglyceride levels were the lowest in CCPE 2.0 (p < 0.05). In the group supplemented with CCPE at all levels, the high-density lipoprotein levels significantly increased (p < 0.05). Drip loss in the breast at 24 and 48 h decreased (p < 0.05). Additionally, live weight, defeathered weight, and carcass weight significantly increased (p < 0.05). Furthermore, CCPE improved intestinal morphology, especially villus height and the villus height per crypt depth ratio (p < 0.05). CCPE supplementation also reduced pathogenic bacteria, increased Lactobacillus spp. (p < 0.05), and increased the expression of immune-related genes and antioxidant activity in the liver and intestines (p < 0.05). Therefore, the use of CCPE as an alternative to antibiotics in broiler feed improved growth performance and health parameters in broilers. It provides a sustainable and environmentally friendly option for supplementary feed, contributing to more efficient poultry nutrition management.

Humic acid from vermicompost effectively regulates the redox status and mitigates the progression of experimental periodontitis.

The progression of periodontal disease (PD) involves the action of oxidative stress mediators. Antioxidant agents may potentially attenuate the development of this condition. Thus, we aimed to evaluate the effects of different doses of humic acid (HA), extracted from biomass vermicomposting, on redox status and parameters related to PD progression in rats. Fifty-four adult male Wistar rats were distributed into six experimental groups (control; PD; PD + 40mg/kg of HA; PD + 80mg/kg of HA; PD + 160mg/kg of HA; PD + 320mg/kg of HA). HA was administered by gavage for 28days, and PD was induced by ligature on the mandibular first molars on the 14th day of treatment. After euthanasia, alveolar bone loss, oxidative stress in the gum and erythrocytes, serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and creatinine were analyzed. Animals treated with HA showed less bone loss at the dose of 80mg/kg compared to the untreated PD group (p < 0.05). Animals treated with HA at doses higher than 80mg/kg showed improvements in local and systemic redox status parameters (total antioxidant activity, thiobarbituric reactive substances, carbonyl derivatives, and superoxide dismutase) compared to the PD group (p < 0.05). Treatment with HA reduced serum levels of creatinine (at doses of 80 and 160mg/kg) and AST (at doses of 40 and 80mg/kg) compared to the PD group (p < 0.05). HA treatment attenuated alveolar bone loss and improved local and systemic oxidative stress parameters in ligature-induced PD rats.

Metformin Alleviates Doxorubicin-Induced Cardiotoxicity via Preserving Mitochondrial Dynamics Balance and Calcium Homeostasis.

Doxorubicin (DOX) is a commonly used chemotherapeutic medication for treating malignancies, although its cardiotoxicity limits its use. There is growing evidence that alteration of the mitochondrial fission/fusion dynamic processes accompanied by excessive reactive oxygen species (ROS) production and alteration of calcium Ca2+ homeostasis are potential underlying mechanisms of DOX-induced cardiotoxicity (DIC). Metformin (Met) is an AMP-activated protein kinase (AMPK) activator that has antioxidant properties and cardioprotective effects. The purpose of the study is to assess Met's possible cardioprotective benefits against DOX-induced cardiotoxicity. The study included 32 adult male rats. They were randomly divided into four groups: administered saline, DOX, Met, or DOX combined with Met respectively. Heart tissues were used for biochemical assays that measured oxidative stress markers, malondialdehyde (MDA), reduced glutathione (GSH), mitochondrial dynamics markers, optic atrophy-1(OPA-1) and dynamin-1-like protein (Drp1), calcineurin and caspase-3. Serum levels of myocardial injury markers, cardiac troponin I (cTn-I), and aspartate aminotransferase (AST), were also measured. The results revealed that DOX intoxication was associated with a significant increase in the levels of serum cTn-I and AST, increased cardiac MDA level, increased cardiac Drp1, calcineurin, and caspase-3 expressions, as well as reduced cardiac GSH level and cardiac OPA-1 expression. On the other hand, Met treatment significantly reduced DIC by decreasing oxidative stress, apoptosis, and improving mitochondrial and calcium balance. Finally, this study shows that Met may be able to protect the heart from damage caused by DOX by working as an antioxidant and anti-apoptotic agent and keeping the balance of calcium and mitochondria.

Coenzyme Q and Selenium Co-Supplementation Alleviate Methionine Choline-Deficient Diet-Induced Metabolic Dysfunction-Associated Steatohepatitis in Mice.

The pathogenesis of metabolic dysfunction-associated steatohepatitis (MASH) is closely associated with increased oxidative stress and lipid peroxidation. Coenzyme Q (CoQ) and selenium (Se) are well-established antioxidants with protective effects against oxidative damage. This study aimed to investigate the effects of CoQ and Se in ameliorating MASH induced by a methionine choline-deficient (MCD) diet in mice. C57BL/6J male mice were fed either a methionine choline-sufficient (MCS) or MCD diet and treated with vehicle, CoQ (100 mg/kg), Se (158 μg/kg), or their combination (CoQ + Se) for 4 weeks. The MCD diet significantly increased hepatic steatosis, inflammation, and fibrosis compared to MCS controls. Treatment with CoQ and Se, particularly in combination, markedly reduced the MAFLD activity score, hepatic inflammation, and fibrosis. Combined supplementation of CoQ and Se significantly decreased serum alanine aminotransferase and aspartate aminotransferase levels and hepatic TG and cholesterol concentrations. CoQ and Se effectively mitigated hepatic oxidative stress by enhancing catalase and superoxide dismutase activities, increasing glutathione peroxidase (GPX) activity, and restoring the GSH/GSSG ratio. Lipid peroxidation markers, such as malondialdehyde and 4-hydroxynonenal, were significantly reduced. Furthermore, the expression of ferroptosis-related markers, including acyl-CoA synthetase long-chain family member 4, arachidonate 12-lipoxygenase, and hepatic non-heme iron content, was significantly downregulated, while GPX4 expression was upregulated by combined CoQ and Se treatment. CoQ and Se synergistically alleviate MASH progression by reducing oxidative stress and lipid peroxidation, which may contribute to the suppression of ferroptosis. Combined CoQ and Se supplementation demonstrates therapeutic potential for managing MASH and related liver injury.