Liver Research Articles

Synthesis and In Vivo Profiling of Desymmetrized Antimalarial Trioxolanes with Diverse Carbamate Side Chains.

The recent withdrawal of artefenomel from clinical development leaves no endoperoxide-class agents in the antimalarial pipeline. Synthetic endoperoxides with a desymmetrized structure have demonstrated promising physiochemical and in vivo properties. Here we expand on our initial investigation of trans-3″ carbamate substitution with a diverse array of amine-, alcohol-, and sulfinyl-terminated analogues prepared in (S,S) and (R,R) configurations. In general, this chemotype combines low-nM antiplasmodial activity with excellent aqueous solubility but widely varying human liver microsome (HLM) stability. We evaluated 20 novel analogues in the P. berghei mouse malaria model, identifying new analogues such as RLA-4767 (9a) and RLA-5489 (9d), with HLM stability and pharmacokinetic profiles superior to analogues from our initial report (e.g., RLA-4776, 8a). These new leads approach or equal the efficacy of artefenomel after two daily oral doses of 10 mg/kg, thus revealing a promising chemotype with the potential to deliver development candidates.

Non-additivity of the functional properties of individual P450 species and its manifestation in the effects of alcohol consumption on the metabolism of ketamine and amitriptyline

To explore functional interconnections between multiple P450 enzymes and their manifestation in alcohol-induced changes in drug metabolism, we implemented a high-throughput study of correlations between the composition of the P450 pool and the substrate saturation profiles (SSP) of amitriptyline and ketamine demethylation in a series of 23 individual human liver microsomes preparations from donors with a known history of alcohol consumption. The SSPs were approximated with linear combinations of three Michaelis-Menten equations with globally optimized KM (substrate affinity) values. This analysis revealed a strong correlation between the rate of ketamine metabolism and alcohol exposure. For both substrates, alcohol consumption caused a significant increase in the role of the low-affinity enzymes. The amplitudes of the kinetic components and the total rate were further analyzed for correlations with the abundance of 11 major P450 enzymes assessed by global proteomics. The maximal rate of metabolism of both substrates correlated with the abundance of CYP3A4, their predicted principal metabolizer. However, except for CYP2D6 and CYP2E1, responsible for the low-affinity metabolism of ketamine and amitriptyline, respectively, none of the other potent metabolizers of the drugs revealed a positive correlation. Instead, in the case of ketamine, we observed negative correlations with the abundances of CYP1A2, CYP2C9, and CYP3A5. For amitriptyline, the data suggest inhibitory effects of CYP1A2 and CYP2A6. Our results demonstrate the importance of functional interactions between multiple P450 species and their decisive role in the effects of alcohol exposure on drug metabolism.

Cardiolipin deficiency disrupts CoQ redox state and induces steatohepatitis.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a progressive disorder marked by lipid accumulation, leading to steatohepatitis (MASH). A key feature of the transition to MASH involves oxidative stress resulting from defects in mitochondrial oxidative phosphorylation (OXPHOS). Here, we show that pathological alterations in the lipid composition of the inner mitochondrial membrane (IMM) directly instigate electron transfer inefficiency to promote oxidative stress. Specifically, cardiolipin (CL) was downregulated across four mouse models of MASLD. Hepatocyte-specific CL synthase knockout (CLS-LKO) led to spontaneous MASH with elevated mitochondrial electron leak. Loss of CL interfered with the ability of coenzyme Q (CoQ) to transfer electrons, promoting leak primarily at sites II F and III Q0 . Data from human liver biopsies revealed a highly robust correlation between mitochondrial CL and CoQ, co-downregulated with MASH. Thus, reduction in mitochondrial CL promotes oxidative stress and contributes to pathogenesis of MASH.

Combining full-length transcriptome sequencing and next generation sequencing to provide insight into the growth superiority of the hybrid grouper (Cromileptes altivelas (♀) × Epinephelus lanceolatus (♂)).

The hybrid grouper (Cromileptes altivelas, ♀ × Epinephelus lanceolatus, ♂) is an economically important aquaculture species that exhibits certain growth advantages compared to its female parent, Cromileptes altivelas. However, the current understanding of the molecular mechanisms underlying the growth of hybrid groupers is lacking. Herein, we performed full-length transcriptome sequencing and next-generation sequencing on the hybrid grouper and its parents to identify growth-related genes and comprehensively analyze the regulatory mechanism of growth heterosis in the hybrid grouper. Approximately 44.70, 40.44, and 45.32 Gb of single-molecule real-time sequencing data were generated in C. altivelas (Cal), E. lanceolatus (Ela), and the hybrid (Hyb), which were combined into 204,322 non-redundant isoforms using the PacBio sequencing platform. Differentially expressed genes (DEGs) were identified between Hyb and Cal (3,494, 2,125, and 1,487 in brain, liver, and muscle tissues, respectively) and Hyb and Ela (3,415, 2,351, and 1,675 in brain, liver, and muscle tissues, respectively). Then, 27 DEGs (13 in the brain and 14 in the muscle) related to growth traits were identified using cluster and correlation network analysis. Quantitative RT-PCR validated 15 DEGs consistent with transcriptome sequencing (RNA-seq) trends. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that these 15 genes were mainly involved in regulating the actin cytoskeleton, suggesting that this pathway plays an essential role in fish growth. In addition, we found that the phosphatase and tensin homologue (PTEN) is a key regulator of growth heterosis in Hyb. These results shed light on the regulatory mechanism of growth in the Hyb, which is important for marker-assisted selection programs to improve the growth quality of groupers.

Leonurine Inhibits Hepatic Lipid Synthesis to Ameliorate NAFLD via the ADRA1a/AMPK/SCD1 Axis.

Leonurine is a natural product unique to the Lamiaceae plant Leonurus japonicus Houtt., and it has attracted attention due to its anti-oxidative stress, anti-apoptosis, anti-fibrosis, and metabolic regulation properties. Also, it plays an important role in the prevention and treatment of nonalcoholic fatty liver disease (NAFLD) through a variety of biological mechanisms, but its mechanism of action remains to be elucidated. Therefore, this study aims to preliminarily explore the mechanisms of action of leonurine in NAFLD. Mice were randomly divided into four groups: the normal control (NC) group, the Model (M) group, the leonurine treatment (LH) group, and the fenofibrate treatment (FB) group. The NAFLD model was induced by a high-fat high-sugar diet (HFHSD) for 12 weeks, and liver pathological changes and biochemical indices were observed after 12 weeks. Transcriptomic analysis results indicated that leonurine intervention reversed the high-fat high-sugar diet-induced changes in lipid metabolism-related genes such as stearoyl-CoA desaturase 1 (Scd1), Spermine Synthase (Sms), AP-1 Transcription Factor Subunit (Fos), Oxysterol Binding Protein Like 5 (Osbpl5), and FK506 binding protein 5 (Fkbp5) in liver tissues. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis results suggest that leonurine may exert its lipid-lowering effects through the AMP-activated protein kinase (AMPK) signaling pathway. Liver lipidomic analysis showed that leonurine could alter the abundance of lipid molecules related to fatty acyl (FAs) and glycerophospholipids (GPs) such as TxB3, carnitine C12-OH, carnitine C18:1-OH, and LPC (20:3/0:0). Molecular biology experiments and molecular docking techniques verified that leonurine might improve hepatic lipid metabolism through the alpha-1A adrenergic receptor (ADRA1a)/AMPK/SCD1 axis. In summary, the present study explored the mechanism by which leonurine ameliorated NAFLD by inhibiting hepatic lipid synthesis via the ADRA1a/AMPK/SCD1 axis.

Dietary bamboo charcoal powder ameliorates high-fat diet-induced hyperlipidemia by enhancing fecal lipid excretions in Sprague-Dawley rats.

Bamboo charcoal powder (BCP) is increasingly used as a food colorant. This study aims to evaluate the effects of BCP consumption on improving high-fat diet-induced hyperlipidemia. Fifty male SD rats were randomly assigned into five groups, with 10 rats in each group: the control group was fed a low-fat diet (LFD); the model control group was fed a high-fat diet (HFD); the low-BCP dose group was fed a HFD and given 2.81 g of BCP/kg of body weight (BCP-L) by gavage; the medium-BCP dose group was fed a HFD and given 5.62 g of BCP/kg of body weight (BCP-M) by gavage; the high-BCP dose group was fed a HFD and given 11.24 g of BCP/kg of body weight (BCP-H) by gavage. After 90 days, the consumption of BCP caused a decrease in body weight, plasma lipids (triglyceride, cholesterol, and low-density lipoprotein (LDL)), liver triglyceride, and cholesterol levels, and liver histopathological scores. BCP caused a significant increase in superoxide dismutase (SOD) activity and total antioxidant capacity (T-AOC) in liver tissues. BCP also led to an increase in 72-h fecal dry weight and crude fat in a rat metabolic cage. The analysis of fecal samples with liquid chromatography time-of-flight mass spectrometry (LC-Q-TOF-MS) showed that the biomarkers associated with BCP consumption were mainly related to fatty and amino acid metabolism. Notably, BCP treatment significantly promoted linoleic acid metabolism. These results suggest that BCP may have a preventive effect against diet-induced hyperlipidemia through the promotion of fecal fat excretion. BCP may potentially be used as an alternative functional food component for people with diet-induced hyperlipidemia.

Severe hypophosphatemia induced by excessive production of FGF23 in acute hepatitis: from bedside to bench

ABSTRACT Background Although hepatic production of FGF23 has been suggested in chronic settings, there are no data indicating hypophosphatemia resulting from acute hepatic FGF23 production. Based on two clinical observations of profound hypophosphatemia in the setting of acute hepatitis, our study investigates the hypothesis of acute FGF23 liver expression. Methods Retrospective analyses were conducted to estimate FGF23 liver expression both qualitatively (in situ hybridization) and quantitatively (relative FGF23 gene expression and protein production) on histological specimens of human and murine acute hepatitis livers, compared with controls of hepatic fibrosis or healthy liver. Results The index clinical case involves acute alcoholic hepatitis complicated by profound hypophosphatemia due to phosphate diabetes, revealing a major production of both FGF23 C-terminal fraction (cFGF23) and bio-intact form (iFGF23, 39 751 RU/mL, N: 21–91; and 228.6 pg/mL, N: 22.7–93.1, respectively). A second case of acute hepatitis related to erythrocytic protoporphyria also exhibited comparable abnormalities. In both cases, no other cause of renal phosphate wasting was identified, and the hydroelectrolytic disorders disappeared in parallel with normalization of the liver balance and FGF23 levels. Histological data of acute hepatitis compared with cirrhosis and healthy liver confirmed our hypothesis of hepatic FGF23 overproduction. Furthermore, mouse models showed a significant increase in FGF23 mRNA relative liver expression in acute hepatitis and a moderate increase in cirrhosis, compared with healthy liver (respectively 60.55 ± 16.75 and 3.70 ± 0.87 vs 1.00 ± 0.65, both P < .05). These findings were also confirmed at the protein level. Conclusion This translational study raises the hypothesis of renal phosphate wasting induced by excessive hepatic production of FGF23 in case of acute hepatitis.

Thyme and Oregano Oil Potential Therapeutics against Malathion Toxicity through Biochemical, Histological, and Cytochrome P450 1A2 Activities in Male Wistar Rats.

The widespread use of malathion may offer several hazards to humans and animals; additionally, many medicinal plants provide what is known as a broad antitoxicity treatment. This study was carried out to investigate hazardous biochemical and histological reactions to MOP and evaluate the effectiveness of TEO and OEO essential oils in restoring normal physiological conditions after MOP exposure by measuring enzyme-specific activity for Cytochrome P450 1A2 (CYP1A2). One hundred and twenty rats were divided into six groups of twenty animals each: (i) C - MOP served as the control group, (ii) C + MOP treated with 5 mg/kg/BW of Malathion-D10, (iii) TEO treated with 100 mg/kg/BW of oregano essential oil, (iv) TEO treated with 100 mg/kg/BW of thyme essential oil, (v) MOP + OEO treated with 5 mg/kg/BW of Malathion-D10 and 100 mg/kg/BW of oregano essential oil, and (vi) MOP + TEO treated with 5 mg/kg/BW of Malathion-D10 and 100 mg/kg/BW of thyme essential oil. The results indicated the protective effects of OEO and TEO against MOP-induced weight loss. Additionally, there was a significant improvement in ALT, AST, and ALK-Ph after being treated with OEO and TEO, either alone or after MOP exposure. Also, treatment with OEO and TEO ameliorated these oxidative stress parameters, indicating their antioxidative properties. A histopathological examination of liver tissues showed reduced hepatocellular damage and improved liver architecture in the OEO and TEO, both alone and in combination with MOP, and protective effects were more pronounced in the TEO-treated groups. However, the results indicated that TEO was more effective than OEO in increasing CYP1A2 expression and alleviating MOP-induced toxicity. Specifically, TEO showed higher protein expression and therapeutic action in reducing liver damage. In conclusion, these findings suggest that OEO and TEO may be potent therapeutic agents against MOP toxicity, offering protective effects by enhancing CYP1A2 activity and mitigating organ damage. Such knowledge would be an important step toward developing potentially unique treatment options for natural antitoxins.

Identification of the effects of hypoxia on the liver tissues of Nile tilapia Oreochromis Niloticus

BackgroundHypoxia stress resulted in mortality during the fish aquaculture program, affecting the sustainable development of the aquaculture industry. The Egyptian strain of O. niloticus showed a strong ability to hypoxia. In this study, a Nile tilapia strain that was kept and selected for 45 years by the author’s team was used to elucidate the mechanism of the hypoxia response in the liver, including the identification of metabolic pathways and genes, involved in the hypoxia response of this strain.ResultsThe effects of hypoxia stress were detected at 0-hour, 6-hour, and 72-hour time points (0 h, 6 h, 72 h) on tilapia liver at 1 mg/L dissolved oxygen conditions. The blood triglyceride, blood glucose and cholesterol values exhibited significantly different change trends, but the hemoglobin content showed no significant differences between 0 h, 6 h and 72 h (P > 0.05). The activities of catalase (CAT), glutathione peroxidase (GSH-PX), total antioxidant capacity (T-AOC), lactate dehydrogenase (LDH), and acid phosphatase (ACP) in the liver tissue gradually increased at 0 h, 6 h and 72 h (P < 0.05). Histological analyses revealed structural changes in intracellular lipid droplets, nuclear migration and dissolution, and cell vacuolization in liver tissues. Six pathways were identified as the main enriched metabolic pathways according to the transcriptome profiling analysis, which were protein processing in endoplasmic reticulum, steroid biosynthesis, peroxisome, PPAR signaling pathway, glycolysis/gluconeogenesis and Insulin signaling pathway. The expressions of the important differentially expressed genes were verified by qPCR analysis, including erola, LOC100692144, sqle, cratb, pipox, cpt1a2b, hik and acss2l, ehhadh, prkcz, fasn and plaa, which showed the same expressions trends as those of RNA-Seq.ConclusionsThe Nile tilapia strain improves the abilities of hypoxia response through energy metabolism. Antioxidant enzyme measurements in the liver indicate that these five antioxidant enzymes play important roles in protecting the body from hypoxic damage. The histological changes in liver cells indicate that the damage caused by hypoxia stress. The immune-related metabolic pathways and energy metabolism-related pathways were obtained by transcriptome profiling, and these metabolic pathways and the differentially expressed genes selected from these metabolic pathways may be involved in the mechanism of hypoxia tolerance in this strain. These findings provide a better understanding of the hypoxia response mechanism of fish, and represent a useful resource for the genetic breeding of O. niloticus.

Ultra-Small Copper-Based Multienzyme-Like Nanoparticles Protect Against Hepatic Ischemia-Reperfusion Injury Through Scavenging Reactive Oxygen Species in Mice.

Hepatic ischemia-reperfusion injury (IRI) is a severe complication that occurs in the process of liver transplantation, hepatectomy, and other end-stage liver disease surgery, often resulting in the failure of surgery operation and even patient death. Currently, there is no effective way to prevent hepatic IRI clinically. Here, it is reported that the ultra-small copper-based multienzyme-like nanoparticles with catalase-like (CAT-like) and superoxide dismutase-like (SOD-like) catalytic activities significantly scavenge the surge-generated endogenous reactive oxygen species (ROS) and effectively protects hepatic IRI. Density functional theory calculations confirm that the nanoparticles efficiently scavenge ROS through their synergistic effects of the ultra-small copper SOD-like activity and manganese dioxides CAT-like activity. Furthermore, the results show that the biocompatible CMP NPs significantly protected hepatocytes from IRI in vitro and in vivo. Importantly, their therapeutic effect is much stronger than that of N-acetylcysteamine acid (NAC), an FDA-approved antioxidative drug. Finally, it is demonstrated that the protective effects of CMP NPs on hepatic IRI are related to suppressing inflammation and hepatocytic apoptosis and maintaining endothelial functions through scavenging ROS in liver tissues. The study can provide insight into the development of next-generation nanomedicines for scavenging ROS.

Effect of curcumin and cacao extract on interleukin-6 expression on ribociclib-induced hepatotoxicity in rats

Purpose: To assess the relationship between interleukin-6 (IL-6) expression and the protective effect of curcumin and cacao extract on hepatotoxicity caused by ribociclib. Method: Sixty adult male albino rats (9 – 10 weeks old) were utilized in this experiment. The rats were separated into six groups (n = 10 each). Group 1 (control) rats received 2 mL of normal saline daily. Group 2 rats were administered 5 mg/kg ribociclib and group 3 rats received 5 mg/kg ribociclib with a cacao dose of 200 mg/kg daily. Group 4 rats were administered 5 mg/kg ribociclib treated with curcumin (200 mg/kg) daily. Groups 5 and 6 were administered cacao and curcumin doses of 200 mg/kg daily. All rats were sacrificed and liver immunohistochemical and histological examinations were performed. Result: The findings demonstrated that ribociclib administration caused liver damage and morphological changes at a histological level in liver tissue. The immunohistochemical investigation revealed that IL-6 levels were significantly increased in group 2 and control group (p &lt; 0.05). Furthermore, co-administration of curcumin and cacao with ribociclib suppressed the levels of IL-6 expression in the liver tissue of rats compared to control group 1. Conclusion: Co-administration of curcumin and cacao protects the liver against ribociclib-induced liver damage. It is necessary to determine the effect of long-term administration of these extracts on the functions of some organs such as the liver and kidney.

Prior Trichinella spiralis infection protects against Schistosoma mansoni induced hepatic fibrosis.

Schistosomiasis affects approximately 250 million people worldwide, with 200,000 deaths annually. It has been documented that the granulomatous response to Schistosoma mansoni (S. mansoni) oviposition is the root cause of progressive liver fibrosis in chronic infection, in 20% of the patients, and can lead to liver cirrhosis and/or liver cancer. The influence of helminths coinfection on schistosomiasis-induced liver pathological alterations remains poorly understood. Therefore, in this study, we investigated the effect of Trichinella spiralis (T. spiralis) infection on S. mansoni-induced hepatic fibrosis. Thirty adult male Balb-c mice were divided into three groups. Group 1 was left uninfected; group 2 was infected with S. mansoni cercariae and group 3 was orally infected with T. spiralis larvae, then 28 days later, this group was infected with S. mansoni cercariae. All groups were sacrificed at the end of the 8th week post infection with S. mansoni to evaluate the effect of pre-infection with T. spiralis on S. mansoni induced liver fibrosis was evaluated parasitologically (worm burden and egg count in tissues), biochemically (levels of alanine aminotransferase and aspartate aminotransferase), histopathologically (H&E and MT staining, and immunohistochemical staining for the expression of α-SMA, IL-6, IL-1β, IL-17, IL-23, TNF-α, and TGF-β). The results in the present study demonstrated marked protective effect of T. spiralis against S. mansoni induced liver pathology. We demonstrated that pre-infection with T. spirais caused marked reduction in the number of S. mansoni adult worms (3.17 ± 0.98 vs. 18 ± 2.16, P = 0.114) and egg count in both the intestine (207.2 ± 64.3 vs. 8,619.43 ± 727.52, P = 0.009) and liver tissues (279 ± 87.2 vs. 7,916.86 ± 771.34; P = 0.014). Consistently, we found significant reductions in both number (3.4 ± 1.1 vs. 11.8.3 ± 1.22; P = 0.007) and size (84 ± 11 vs. 294.3 ± 16.22; P = 0.001) of the hepatic granulomas in mice pre-infected with T. spiralis larvae compared to those infected with only S. mansoni. Furthermore, pre- infection with T. spiralis markedly reduced S. mansoni- induced hepatic fibrosis, as evidenced by decreased collagen deposition, low expression of α-SMA, and significantly reduced levels of IL-17, IL-1B, IL-6, TGF-B, IL-23, and TNF-α compared to mice infected with S. mansoni only. Our data show that pre-infection with T. spiralis effectively protected mice from severe schistosomiasis and liver fibrosis. We believe that our findings support the potential utility of helminths for the preventing and ameliorating severe pathological alterations induced by schistosomiasis.

Pro-inflammatory cytokines gene expression in liver and kidneys of rats exposed to a sub-lethal dose of Bitis arietans snake venom.

Bitis arietans (Puff adder) is a poisonous snake and its bite causes pain, edema, blistering, tissue damage and neutrophilia. There are limited studies on inflammatory process involved in Bitis arietans envenomation. We therefore investigated the role of proinflammatory cytokines in Bitis arietans venom (BAV)-induced liver and kidney toxicities in rats. Adult male Sprague Dawley rats were treated with BAV (0.5 mg/kg) and were sacrificed after specific time intervals (2 h, 24 h, 1 week). Blood samples were collected for liver and renal function tests and tissues were collected for histopathology and gene expression analysis of IL-1β, IL-6, and TNF-α in liver and kidneys. There was no significant difference in serum ALT activities among different treatment groups. Serum AST was significantly increased at 24 h following BAV injection. In both organs, injection of BAV resulted in mild inflammatory cell infiltration at 2 h post-dosing which normalized after 1 week. In liver, there was a significant increase in IL-1β expression in BAV-treated rats at 2 and 24 h post-dosing that reduced after one week. Significant increases in IL-6 and TNF-α were observed at 24 h and 1 week after BAV exposure. In kidneys, there were significant increases in IL-1β and TNF-α expression at 24 h that subsided after 1 week. In conclusion, a single sub-lethal dose of BAV caused an acute phase inflammation in liver and kidneys. It is most probable that a higher dose of BAV may result in greater and irreversible damage to these organs.

Pathway-Based Similarity Measurement to Quantify Transcriptomics Similarity Between Human Tissues and Preclinical Models.

Accurate clinical translation of preclinical research remains challenging, primarily due to species-specific differences and disease and patient heterogeneity. An important recent advancement has been development of microphysiological systems that consist of multiple human cell types that recapitulate key characteristics of their respective human systems, allowing essential physiologic processes to be accurately assessed during drug development. However, an unmet need remains regarding a quantitative method to evaluate the similarity between diverse sample types for various contexts of use (CoU)-specific pathways. To address this gap, this study describes the development of pathway-based similarity measurement (PBSM), which leverages RNA-seq data and pathway-based information to assess the human relevance of preclinical models for specific CoU. PBSM offers a quantitative method to compare the transcriptomic similarity of preclinical models to human tissues, shown here as proof of concept for liver and cardiac tissues, enabling improved model selection and validation. Thus, PBSM can successfully support CoU selection for preclinical models, assess the impact of different gene sets on similarity calculations, and differentiate among various in vitro and in vivo models. PBSM has the potential to reduce the translational gap in drug development by allowing quantitative evaluation of the similarity of preclinical models to human tissues, facilitating model selection, and improving understanding of context-specific applications. PBSM can serve as a foundation for enhancing the physiological relevance of in vitro models and supporting the development of more effective therapeutic interventions.

DELE1 maintains muscle proteostasis to promote growth and survival in mitochondrial myopathy.

Mitochondrial dysfunction causes devastating disorders, including mitochondrial myopathy, but how muscle senses and adapts to mitochondrial dysfunction is not well understood. Here, we used diverse mouse models of mitochondrial myopathy to show that the signal for mitochondrial dysfunction originates within mitochondria. The mitochondrial proteins OMA1 and DELE1 sensed disruption of the inner mitochondrial membrane and, in response, activated the mitochondrial integrated stress response (mt-ISR) to increase the building blocks for protein synthesis. In the absence of the mt-ISR, protein synthesis in muscle was dysregulated causing protein misfolding, and mice with early-onset mitochondrial myopathy failed to grow and survive. The mt-ISR was similar following disruptions in mtDNA maintenance (Tfam knockout) and mitochondrial protein misfolding (CHCHD10 G58R and S59L knockin) but heterogenous among mitochondria-rich tissues, with broad gene expression changes observed in heart and skeletal muscle and limited changes observed in liver and brown adipose tissue. Taken together, our findings identify that the DELE1 mt-ISR mediates a similar response to diverse forms of mitochondrial stress and is critical for maintaining growth and survival in early-onset mitochondrial myopathy.

The effect of probiotic supplementation on non-alcoholic fatty liver disease (NAFLD) fibrosis score in patients attending a tertiary hospital clinic in Cairo, Egypt.

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic fat accumulation (> 5% of liver tissue) in the absence of alcohol abuse or other chronic liver diseases. NAFLD can progress to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). This study aimed to assess the efficacy of probiotic (lactobacillus) supplementation on NAFLD fibrosis score. A double-arm randomized controlled trial was conducted in the family medicine clinic of a tertiary hospital, enrolling patients with sonographic evidence of NAFLD. Fifty patients were divided into two groups: the Probiotic group received lifestyle modification instructions along with daily probiotic supplementation for twelve weeks, with regular monthly follow-up visits. The Standard Treatment group received low-fat diet and lifestyle modification instructions only. The mean age of participants was 46.10 years (SD 10.11), with 70% females and 30% males. The study found a statistically significant difference in liver enzymes (ALT and AST) and BMI in the probiotic group before and after intervention. However, there was no significant difference in NAFLD fibrosis score between the two groups. Short-term probiotic treatment resulted in improvements in ALT, AST, and BMI in the probiotic group, but did not significantly affect NAFLD fibrosis score. Further research with larger sample sizes and longer follow-up periods is warranted. The clinical trial was registered at Protocol Registration and Results System with number NCT06074094 (12/09/2021).

Comparative study of immune responses and intestinal microbiota in the gut-liver axis between wild and farmed pike perch (Sander Lucioperca).

Pike perch (Sander Lucioperca) is a predatory freshwater fish, which is highly popular amongst consumers, owing to its white flesh with a delicate structure and mild flavor. Compared to wild pike perch, the diet of farmed ones has shifted from natural food to artificial feeds. These changes would affect the gut flora of the pike perch. Endogenous metabolites of the intestinal flora are transferred through the gut-liver axis, which affects the physiological functions of the host. By studying wild and farmed individuals of the pike perch, novel insights into the stability of the intestinal flora can be provided. In this study, we measured various immune parameters in the blood, liver and intestine of wild and farmed pike perch using enzyme activity assays and real-time fluorescence quantitative PCR. Gut microbes were also collected for 16S rRNA gene sequencing. Our results showed that the serum low-density lipoprotein cholesterol (LDL-C) levels were twice as high in the wild group as in the farmed group. Furthermore, the activities of glutamate pyruvate transaminase (GPT) and glutamate oxaloacetate transaminase (GOT) in the intestinal tissues of the wild group were 733.91 U/g and 375.35 U/g, which were significantly higher than those of the farmed group. Expression of IL10 in the liver of farmed pike perch was also 4-fold higher than that of wild pike perch. The expression of genes related to the p53-BAX/Bcl2 signaling pathway was higher in both intestinal and liver tissues of wild pike perch compared with farmed. 16S rRNA gene analysis of the gut microflora showed a high relative abundance of Cetobacterium in the gut of farmed pike perch. As a result, our study indicates that dietary differences affect the diversity, composition and relative abundance of the gut flora of the pike perch. Meanwhile, it affects the glycolipid metabolism and immunomodulation of pike perch.

D-Xylose Ameliorates Non-Alcoholic Fatty Liver Disease by Targeting Macrophage-expressed LYZ Gene.

This study investigates the therapeutic effects of D-Xylose, a natural sugar, on non-alcoholic fatty liver disease (NAFLD), focusing on the expression of the lysozyme gene (LYZ) in macrophages. Using the single-cell dataset GSE136103 for NAFLD, researchers analyzed macrophage populations and other groups utilizing the Seurat package in R, while a differential analysis was performed on the NAFLD dataset GSE61260 using the limma package. Both in vitro and in vivo models, including cell culture, mouse models, RT-qPCR, Western blot, ELISA, and histopathological analyses, were employed to examine the effect of D-Xylose on lipid accumulation, LYZ expression, blood lipid levels, and inflammatory responses. The study found a significant upregulation of LYZ in free fatty acid (FFA)-treated cells and mouse liver tissues, with a subsequent reduction after D-Xylose intervention. Treatment with D-Xylose and Amlodipine led to a notable decrease in lipid accumulation, as evidenced by reduced triglyceride and cholesterol levels. D-Xylose demonstrated a greater improvement in lipid metabolism than Amlodipine. Additionally, D-Xylose significantly mitigated inflammatory responses, reducing levels of inflammatory markers such as IL1R, IL6, MYS8, TNF, NF-κB, and IL-1. Furthermore, D-Xylose administration significantly reduced liver weight and liver index, with a positive impact on serum liver function and blood lipid levels. The findings suggest that D-Xylose could be a therapeutic intervention for NAFLD by targeting LYZ expression in macrophages, thereby modulating lipid metabolism and inflammatory responses.

Metastatic organotropism in small cell lung cancer.

Metastasis is the leading cause of cancer-related deaths, yet its regulatory mechanisms are not fully understood. Small-cell lung cancer (SCLC) is the most metastatic form of lung cancer, with most patients presenting with widespread disease, making it an ideal model for studying metastasis. However, the lack of suitable preclinical models has limited such studies. We utilized well-annotated rapid autopsy-derived tumors to develop xenograft models that mimic key features of SCLC, including histopathology, rapid and widespread development of metastasis to the liver, brain, adrenal, bone marrow, and kidneys within weeks, and response to chemotherapy. By integrating in vivo lineage selection with comprehensive transcriptomic and epigenomic analyses, we identified critical cellular programs driving metastatic organotropism to the liver and brain, the most common sites of SCLC metastasis. Our findings reveal the key role of nuclear-cytoskeletal interactions in SCLC liver metastasis. Specifically, the loss of the nuclear envelope protein lamin A/C, encoded by the LMNA gene, increased nuclear deformability and significantly increased the incidence of liver metastasis. Human liver metastases exhibited reduced LMNA expression compared to other metastatic sites, correlating with poorer patient outcomes and increased mortality. This study introduces novel preclinical models for SCLC metastasis and highlights pathways critical for organ-specific metastasis, offering new avenues for the development of targeted therapies to prevent or treat metastatic disease.

The Critical Role of Regulatory T Cells in Immune Tolerance and Rejection Following Liver Transplantation: Interactions With the Gut Microbiome.

Liver transplantation (LT) is the ultimate treatment for patients with end-stage liver disease or early hepatocellular carcinoma. In the context of LT, because of the unique immunological characteristics of human liver allograft, 5%-20% of selected LT recipients can achieve operational tolerance. Nonetheless, there remains a risk of rejection in LT patients. Maintaining immune homeostasis is thus crucial for improving clinical outcomes in these patients. In mechanism, several immune cells, including dendritic cells, Kupffer cells, myeloid-derived suppressor cells, hepatic stellate cells, regulatory B cells, and CD4+ regulatory T cells (Treg), contribute to achieving tolerance following LT. In terms of Treg, it plays a role in successfully minimizing immunosuppression or achieving tolerance post-LT while also reducing the risk of rejection. Furthermore, the gut microbiome modulates systemic immune functions along the gut-liver axis. Recent studies have explored changes in the microbiome and its metabolites under various conditions, including post-LT, acute rejection, and tolerance. Certain functional microbiomes and metabolites exhibit immunomodulatory functions, such as the augmentation of Treg, influencing immune homeostasis. Therefore, understanding the mechanisms of tolerance in LT, the role of Treg in tolerance and rejection, as well as their interactions with gut microbiome, is vital for the management of LT patients.