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PubMed2026

Targeting microbial bile salt hydrolase reprograms bile acid metabolism and ameliorates metabolic dysfunction-associated steatohepatitis in mice.

Microbial bile salt hydrolase (BSH) plays a central role in shaping bile acid composition and gut-liver metabolic signaling, yet its therapeutic potential in metabolic dysfunction-associated steatohepatitis (MASH) remains incompletely defined. Here, we evaluated the efficacy of the non-absorbable BSH inhibitor GR-7 in a diet-induced mouse model of steatohepatitis using early and late intervention strategies with different dosing regimens. GR-7 reduced food intake and exerted stage- and dose-dependent therapeutic effects, with early intervention robustly suppressing hepatic fibrosis even at a low dose, whereas late-stage administration of high-dose GR-7 markedly reduced hepatic steatosis and inflammation, as evidenced by decreased liver weight, hepatic triglyceride and cholesterol levels, and plasma ALT. Although late intervention did not result in statistically significant histological reversal of fibrosis, a trend toward improvement was observed, together with suppression of fibrogenic gene expression, suggesting that prolonged treatment may further enhance antifibrotic efficacy. Mechanistically, GR-7 effectively inhibited microbial BSH activity in vivo, leading to reduced cecal unconjugated primary and secondary bile acids-including deoxycholic acid and lithocholic acid, which was associated with improved gut barrier integrity and reduced hepatic inflammation. In parallel, BSH inhibition reprogrammed hepatic bile acid metabolism toward activation of the alternative CYP27A1-mediated synthesis pathway, accompanied by reduced food intake, thereby contributing to reduced hepatic lipid accumulation. Furthermore, late-stage high-dose treatment selectively remodeled the hepatic immune landscape rather than fully restoring homeostasis, highlighting immune recalibration as a key component of therapeutic response. Together, these findings identify microbial BSH inhibition as a promising microbiome-targeted therapeutic strategy for MASH.

Animals↗

PubMed2025

Immunopathogenic mechanisms and immunoregulatory therapies in MASLD.

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), is the most prevalent chronic liver disease worldwide, with an estimated global prevalence of approximately 30%; however, effective pharmacotherapies are still limited due to its complex pathogenesis and etiology. Therefore, a more thorough understanding of disease pathogenesis is urgently needed. An increasing number of studies suggest that MASLD and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), are driven by chronic overnutrition, multiple genetic susceptibility factors, and pathogenic consequences, including hepatocyte damage and liver inflammation. Hepatic inflammation is the key event fueling the conversion from simple steatosis to steatohepatitis and fibrosis. Current therapies for MASH, including the recently approved thyroid hormone receptor-beta agonist resmetirom or the available incretin mimetics, mainly target metabolic injury to the liver but not inflammation directly. In this review, we provide an in-depth discussion of current data related to the immunological mechanisms of MASLD and summarize the effects of current and experimental therapies on immunoregulation in MASLD.

Humans↗

PubMed2026

Targeting Microbial Bile Salt Hydrolase Reprograms Bile Acid Metabolism and Ameliorates Metabolic Dysfunction-Associated Steatohepatitis in Mice.

Microbial bile salt hydrolase (BSH) plays a central role in shaping bile acid composition and gut-liver metabolic signaling, yet its therapeutic potential in metabolic dysfunction-associated steatohepatitis (MASH) remains incompletely defined. Here, we evaluated the efficacy of the non-absorbable BSH inhibitor GR-7 in a diet induced mouse model of steatohepatitis using early and late intervention strategies with different dosing regimens. GR-7 reduced food intake and exerted stage- and dose-dependent therapeutic effects, with early intervention robustly suppressing hepatic fibrosis even at low dose, whereas late-stage administration of high-dose GR-7 markedly reduced hepatic steatosis and inflammation, as evidenced by decreased liver weight, hepatic triglyceride and cholesterol levels, and plasma ALT. Although late intervention did not result in statistically significant histological reversal of fibrosis, a trend toward improvement was observed, together with suppression of fibrogenic gene expression, suggesting that prolonged treatment may further enhance antifibrotic efficacy. Mechanistically, GR-7 effectively inhibited microbial BSH activity in vivo, leading to reduced cecal unconjugated primary and secondary bile acids-including deoxycholic acid and lithocholic acid, which was associated with improved gut barrier integrity and reduced hepatic inflammation. In parallel, BSH inhibition reprogrammed hepatic bile acid metabolism toward activation of the alternative CYP27A1-mediated synthesis pathway, accompanied by reduced food intake, thereby contributing to improved hepatic lipid accumulation. Furthermore, late-stage high-dose treatment selectively remodeled the hepatic immune landscape rather than fully restoring homeostasis, highlighting immune recalibration as a key component of therapeutic response. Together, these findings identify microbial BSH inhibition as a promising microbiome-targeted therapeutic strategy for MASH.

Gut microbiome↗

PubMed1978

[Demonstration of early local vital reactions by combination of morphological investigation methods (author's transl)].

In extension of earlier Scanning Electron Microscopical findings on local vital reaction, we initially tried conventional microscopic histology. By standard staining methods--generally used in demonstrating fibrins (Ladew IG, PTAH, PAS etc.) fresh fibrinous mashing was hardly demonstrable. Tryptophan reaction as per Adams brought positive results. By modifying Scanning Electron Microscopic preparation techniques, the surface transverse striation could be shown. For dissolution of the complex morphological structural patterns on the wound surface, Transmission Electron Microscopy was used. Identification of fibrinous filaments was done by their interior transverse striation. Mashing of shaped structure components of the blood in vital and post mortal injuries should be more closely analyzed. Advantages and disadvantages of Scanning and Transmission Electron Microscopic techniques are discussed in view of forensic problems and a tentative judgement passed.

Animals↗

PubMed1977

A rapid quantitative assay for lymphotoxin.

A rapid quantitative assay for lymphotoxin was developed with the use of a mouse cultured lymphoid cell line, L1210 as the target cell. The assay produces results which are substantially in agreement with assays employing fibroblasts as targets. After incubation with lymphotoxin containing samples, target cells were labelled with [3H]thymidine and harvested with a Multiple Automated Sample Harvester (MASH). The MASH allows multiple replicates to be obtained from which the calculation of an I50 (50% inhibition) point and lymphotoxin specific activities can be performed with high statistical reliability by means of probit transformation and analysis.

Animals↗

PubMed1979

Control of instrumental behavior by deprivation stimuli.

In Experiment 1, rats were given one trial per day in a straight alley under food deprivation on half of the trials and under water deprivation on the other half. Wet mash was available in the goal box under food deprivation for Group H and under water deprivation for Group T, the other deprivation being nonrewarded for each group. After 15--18 trials both groups ran significantly faster on their rewarded than on their nonrewarded deprivation days. A third group showed that random variation of alley color retarded formation of the discrimination. A fourth group was run in a conditional discrimination in which under food deprivation wet mash was available in a black alley, nonreward in a white alley, and vice versa under water deprivation. This group took 114 trials to begin running significantly faster in their rewarded than in their nonrewarded alley under each deprivation. In Experiment 2, it was shown that prior learning about deprivation cues "blocks" learning about alley color when alley color is subsequently presented in compound with the deprivation cue but that when both alley color and deprivation cues are relevant from the start of training, the rat learns about both cues. It is suggested that previous studies have underestimated the importance of deprivation cues by using conditional discrimination designs, choice measures rather than speeds, and parameters that are not optimal for discrimination learning.

Animals↗

PubMed2026

pLAST-a tool for rapid comparison and classification of bacterial plasmid sequences.

MOTIVATION: The increasing number of fully sequenced bacterial plasmids being annotated and catalogued has prompted the development of computational tools for comparing and classifying them. Existing approaches typically compare full-length DNA sequences (e.g. Mash, BLASTn, and ANI-based methods) or translated open reading frames (ORFs) (e.g. DIAMOND), with plasmid-level scores obtained by aggregating ORF-to-ORF similarities; however, they are either restricted to closely related plasmids or become computationally demanding in large-scale analyses. RESULTS: We describe pLAST (plasmid Language Analysis and Search Tool), a plasmid-search tool built using word2vec representations of protein-family content informed by local genomic context. Benchmarks indicate that pLAST outperforms nucleotide-based methods and performs comparably to DIAMOND in identifying functionally similar plasmids and compared with the widely used Mash, it achieves 26% and 24% improvements in detecting shared mating-pair formation system type and relaxase type, respectively. This performance scales to database searches across hundreds of thousands of sequences, as demonstrated using the precomputed PlasmidScope collection of ∼750 000 plasmids. Beyond global similarity, pLAST also returns per-ORF plasmid-plasmid alignments, enabling detection of shared functional modules. AVAILABILITY AND IMPLEMENTATION: pLAST is freely accessible as a web server at https://plast.lbs.cent.uw.edu.pl/ or https://plast.lbs.biol.uw.edu.pl/ and available as a Python module along with a precomputed database at https://github.com/labstructbioinf/pLAST for customized analysis.

Plasmids↗

PubMed1977

Statistical analysis and quality control in radioimmunoassays for staphylococcal enterotoxins A, B, and C.

The objective of these studies was to set up a reliable radioimmunoassay (RIA) for staphylococcal enterotoxins A, B, and C (SEA, SEB, and SEC) in a food system. Significant differences (95% confidence limits) were obtained between the 0- and 1-ng/ml enterotoxin standards, so the sensitivity of the RIAs was 1 ng/ml. Polystyrene tubes coated with anti-SEB and stored at 4 degrees C were unstable. The percentage of iodinated SEB bound to these tubes decreased at a rate of 0.33%/day, in contrast to the rate of 0.07%/day obtained with tubes prepared the day before the analyses. Satisfactory precision and maximum sensitivity were obtained by using six replicates for each sample and freshly coated tubes. The antisera used for coating the tubes were reused four times and were frozen between coatings. The process of drum drying mashed potatoes containing 1 mug of SEB per g of mashed potatoes inactivated 83% (wt/wt) of the SEB. Statistical quality control parameters were used to insure that RIAs were performing reliably with a sensitivity of 1 ng/ml. Over 450 samples of potato flakes and granules, which represented different production lots from 12 different manufacturers, were examined for SEA, SEB, and SEC. No enterotoxins were detected.

Cross Reactions↗

PubMed1977

Some observations on oscillatory changes in the growth rate of Saccharomyces cerevisiae in aerobic continuous undisturbed culture.

Oscillatory changes in the growth rate were observed in undisturbed continuous culture of Saccharomyces cerevisiae on sugar-cane molasses media when nitrogen sources (2.56 to 6.17 g/liter of ammonium sulfate or 1.22 g/liter of urea) were added to the feeding mash and when the air rate was 1.3 to 1.6 v/v/m. The oscillations were not affected by the addition of yeast extract. The suppression of the nitrogen source during the continous test leads to a nonoscillatory transient state. No oscillations occured at all when no nitrogen source was added to the medium and/or the air rate was equal to zero or equal to about 3.3 v/v/m. The oscillatory responses of the system were affected by a previous anaerobic continuous cultivation of the yeast.

Aerobiosis↗

PubMed1975

The cockerel as an animal model for atherosclerosis research.

The chicken is a good animal model for the study of atherosclerosis research because it is: 1. Omnivorous. 2. Small and suitable for prolonged laboratory investigation. 3. Able to develop spontaneous atherosclerosis. 4. Capable of producing atherosclerosis after cholesterol feeding with elevated hypercholesterolemia. A diet of 1/4% cholesterol plus 5% cottonseed oil added to starter-grower-mash resulted in aortic atherosclerosis with a slight but significant increase in plasma cholesterol. 5. Plasma levels of cholesterol and triglyceride are similar to those in humans. 6. Lipid composition of high and low density lipoproteins as well as chylomicrons resembles those of humans. 7. Has been noted that there is no essential difference between vascular lesions seen in chickens as a result of cholesterol diet and that of atherosclerosis observed in man.

Animals↗

PubMed1977

[Correlation of cyanogenic glycosides with content of benzyl alcohol in cherry brandies (author's transl)].

A clear correlation between cyanogenic glycosides and the content of benzyl alcohol in fermented mash of cherries was indicated by model experiments with amygdalin and fermenting yeast, cherry-stones with and without fermenting yeasts as well as bitter and sweet almonds. These correlations proofed that benzyl alcohol has to be regarded as a metabolic product of mandelonitrileglycosides.

Alcoholic Beverages↗

PubMed2026

Scorpion venom peptides: Novel therapeutic approaches for inflammatory and hepatic disorders.

Chronic hepatic disorders, such as metabolic dysfunction associated steatohepatitis (MASH), alcohol associated liver disease (ALD), and viral hepatitis (Hepatitis B virus [HBV]/Hepatitis C virus [HCV]), are primarily driven by persistent immune-mediated inflammation and hepatic stellate cell activation leading to fibrosis, yet conventional therapies lack tissue and molecular specificity. Scorpion venom peptides, refined through evolutionary selection, provide highly potent, target specific scaffolds capable of modulating intrahepatic inflammatory networks. Recent in vivo preclinical studies indicate that voltage gated potassium (Kv1.3) channel blocking peptides, such as BmKK2, significantly reduce macrophage activation and inhibit downstream cytokine production, effectively ameliorating diet-induced steatohepatitis and tissue scarring in murine models. Engineered hepatotropic candidates, such as Smp76 and Mucroporin-M1, demonstrate dual therapeutic functions: they neutralize extracellular Hepatitis C particles and suppress key host transcription factors necessary for Hepatitis B replication. This review systematically examines scorpion venom peptides organized by disease category, covering their historical development, structural classification into disulfide-bridged and non-disulfide-bridged families, ion channel specificity, hepatic anti-inflammatory and antiviral mechanisms, and translational challenges including nano-formulation delivery strategies and computational drug design. These target-specific peptides are ultimately positioned as promising molecular leads that may bridge targeted immunomodulation with the resolution of chronic, progressive liver injury.

Anti-inflammatory effects↗

PubMed1979

Distribution of intimal smooth muscle cell masses and their relationship to early atherosclerosis in the abdominal aortas of young swine.

In the abdominal aortas of young mash-fed swine, intimal cell masses (pads, cushions) are located predominantly away from blood vessel orifices. They are found scattered throughout the aorta but nevertheless have a definite pattern of distribution. In the distal one half of the abdominal aorta, they are more frequent in the ventral quandrant than in the dorsal or either lateral quadrant. In the proximal half, intimal cell masses are more frequent in the dorsal quadrant. When experimental atherosclerosis is induced in the abdominal aortas of young swine by either a hypercholesterolemic diet or by aortic ballooning followed by a hypercholesterolemic diet, the distribution of early lesions is similar. The lesions are found predominantly in quadrants where intimal cell masses were found to be most frequent in the control group of swine. The results suggest that most of the lesions, though not necessarily all, arose from pre-existing intimal cell masses beneath the aortic surface.

Animals↗

PubMed1978

Effects of 6-hydroxydopamine lesions of the nucleus accumbens septi and olfactory tubercle on feeding, locomotor activity, and amphetamine anorexia in the rat.

Bilateral 6-hydroxydopamine lesions of the nucleus accumbens septi (NAS) and olfactory tubercle (OT) caused enhanced intake of wet mash in 23-hr-food-deprived rats tested in photocell activity cages during restricted 30-min sessions. This mild hyperphagia was accompanied by a significant hypoactivity in the group with NAS/OT lesions. No hyperphagia was observed during a prolonged 120-min test session or in free-feeding tests conducted in the home cage. Anorexia induced by d-amphetamine (.5 and 1.5 mg/kg) was unaltered by the lesion, although the locomotor stimulant action of the drug was attenuated. A second experiment showed that the NAS/OT lesion also enhanced food intake in the photocell cages during 30-min sessions with dry food pellets but that food-associated drinking was concomitantly reduced. The results are consistent with the hypothesis that the behavioral changes caused by mesolimbic neuron destruction result in part from an inability to switch from one behavioral activity to another.

Anorexia↗

PubMed2025

Immune microenvironment in hepatocellular carcinoma: from pathogenesis to immunotherapy.

Hepatocellular carcinoma (HCC) is an increasingly prevalent and deadly disease that is initiated by different etiological factors, such as alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatohepatitis (MASH), viral hepatitis, and other hepatotoxic and hepatocarcinogenic agents. The tumor microenvironment (TME) of HCC is characterized by several different fibroblastic and immune cell types, all of which affect the initiation, progression and metastasis of this malignant cancer. This complex immune TME can be divided into an innate component that includes macrophages, neutrophils, dendritic cells, myeloid-derived suppressor cells, mucosal-associated invariant T cells, natural killer cells, natural killer T cells, and innate lymphoid cells, as well as an adaptive component that includes CD4+ T cells, CD8+ T cells, regulatory T cells, and B cells. In this review, we discuss the latest findings shedding light on the direct or indirect roles of these immune cells (and fibroblastic-like cells such as hepatic stellate cells) in the pathogenesis of HCC. Henceforth, further characterization of this heterogeneous TME is highly important for studying the progression of HCC and developing novel immunotherapeutic treatment options. In line with this, we also review novel groundbreaking experimental techniques and animal models aimed at specifically elucidating this complex TME and discuss emerging immune-based therapeutic strategies intended to treat HCC and predict the efficacy of these immunotherapies.

Humans↗

PubMed2026

Comparative genomics reveals population structure and functional differentiation in Limosilactobacillus fermentum.

Limosilactobacillus fermentum is a widely distributed lactic acid bacterium frequently detected in fermented foods and host-associated microbiota, yet its global genomic diversity and functional variability remain insufficiently characterized. Here, we performed a large-scale comparative genomic analysis of 336 high-quality L. fermentum genomes curated from public databases. Species identity was validated using average nucleotide identity (ANI), and population structure was examined using pairwise ANI comparisons together with Mash-based phylogenetic reconstruction. Clustering at ≥ 99% ANI resolved the dataset into 15 genomic clusters, with four dominant lineages comprising the majority of genomes. Pangenome reconstruction identified 5,853 gene clusters, including 1,325 core genes (22.6%) and a large accessory component dominated by low-frequency genes. Heap's law modeling (λ = 0.19) indicated a weakly open pangenome, suggesting ongoing gene acquisition as additional genomes are sampled. Functional annotation revealed that core genes were primarily associated with essential cellular processes, whereas accessory genes were enriched in carbohydrate metabolism, membrane-associated functions, and defense-related systems. Variation in carbohydrate-active enzymes (CAZymes), transport systems, and stress-response genes was observed across lineages, indicating strain-level functional diversity. Although genomes from human and food sources were broadly distributed across phylogenetic lineages, multivariate analysis showed that gene-content variation was more strongly associated with genomic lineage than with isolation source. These results provide a population genomic framework for understanding genomic diversity and functional potential in L. fermentum.

Phylogeny↗

PubMed1979

Toxicity of Crotalaria Goreensis for chickens.

Ground Crotalaria goreensis seed fed to day-old cockerel chickens at 3 different rates in a commercial ration of chick starter mash depressed growth rates. Moist faeces were common. Lesions consistently found included ulceration of the proximal large intestine and a dark grey discolouration of the glandular portion of the proventriculus. C. goreensis should be excluded from all poultry rations.

Animal Feed↗

PubMed2026

Loss of Mtarc1 Protects Against Steatotic Liver Disease in Mice.

BACKGROUND & AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) spans from simple steatosis to metabolic dysfunction-associated steatohepatitis (MASH) and can progress to cirrhosis or hepatocellular carcinoma. Despite its prevalence, effective therapies are lacking. Recent genome-wide association studies identified a common missense variant (rs2642438) in the Mitochondrial Amidoxime Reducing Component 1 (MTARC1) gene that protects against liver cirrhosis without increasing cardiovascular disease risk. Biochemical and disease risk signatures associated with carriers of this missense variant also aligned with those of a known loss-of-function MTARC1 variant, suggesting mARC1 inhibition as a potential MASLD treatment. METHODS: To validate mARC1 loss-of-function as protective against MASLD, we generated Mtarc1 knockout (KO) mice and placed them on a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD). Effects of Mtarc1 KO on obesity and type 2 diabetes were explored using a high-fat diet. Hepatocytes from Mtarc1 KO mice were isolated to explore the molecular mechanisms by which Mtarc1 KO impacts lipid metabolism. RESULTS: Mtarc1 KO mice exhibited no vital growth or development defects. With a high-fat diet-induced obesity model, obese Mtarc1 KO mice exhibited reduced liver mass and lower cholesterol levels, with no effect on glucose homeostasis. In a CDAHFD-induced MASLD model, mARC1 deficiency significantly reduced liver steatosis, profibrosis, and inflammation. Untargeted metabolomics profiling further showed hepatic enrichment of phospholipids in Mtarc1 KO mice. Primary hepatocytes isolated from Mtarc1 KO mice exhibited reduced lipid droplet accumulation, decreased fatty acid uptake, and increased lipid secretion. CONCLUSIONS: These findings support mARC1 inhibition as a promising therapeutic strategy for MASLD/MASH.

Animals↗