Search Results (2,163)

Hypothermia-related deaths present significant diagnostic challenges due to non-specific and often inconsistent autopsy findings. This study investigated the histological and immunohistochemical alterations associated with primary and secondary hypothermia in an experimental Rattus norvegicus model, focusing on the effects of benzodiazepine and alcohol ingestion. Twenty-one male rats were divided into three groups: control (K), benzodiazepine-treated (B), and alcohol-treated (A). After two weeks of substance administration, hypothermia was induced and multiple organ samples were analyzed. Histologically, renal tissue showed hydropic and vacuolar degeneration, congestion, and acute tubular injury across all groups, with no significant differences in E-cadherin expression. Lung samples revealed congestion, emphysema, and hemorrhage, with more pronounced vascular congestion in the alcohol and benzodiazepine groups. Cardiac tissue exhibited vacuolar degeneration and protein denaturation, particularly in substance-exposed animals. The spleen showed preserved architecture but increased erythrocyte infiltration and significantly elevated myeloperoxidase (MPO)-positive granulocytes in the intoxicated groups. Liver samples demonstrated congestion, focal necrosis, and subcapsular hemorrhage, especially in the alcohol group. Immunohistochemical analysis revealed statistically significant differences in MPO expression in both lung and spleen tissues, with the highest levels observed in the benzodiazepine group. Similarly, CK7 and CK20 expression in the gastroesophageal junction was significantly elevated in both alcohol- and benzodiazepine-treated animals compared to the controls. In contrast, E-cadherin expression in the kidney did not differ significantly among the groups. These findings suggest that specific histological and immunohistochemical patterns, particularly involving pulmonary, cardiac, hepatic, and splenic tissues, may help differentiate primary hypothermia from substance-related secondary hypothermia. The study underscores the value of integrating toxicological, histological, and molecular analyses to enhance the forensic assessment of hypothermia-related fatalities. Future research should aim to validate these markers in human autopsy series and explore additional molecular indicators to refine diagnostic accuracy in forensic pathology. Full article

Cadmium (Cd) is a toxic environmental heavy metal that exerts harmful effects on multiple tissues, including the kidney, liver, lung, and bone, and is also associated with the development of anemia. However, the precise molecular mechanisms underlying Cd-induced toxicity remain incompletely understood. In this paper, we review the recent molecular mechanisms of Cd-induced toxicity and its modification, with a particular emphasis on our recent findings. Using a combination of DNA microarray analysis, protein–DNA binding assays, and siRNA-mediated gene silencing, we identified several transcription factors, YY1, FOXF1, ARNT, and MEF2A, as novel molecular targets of Cd. The downregulation of their downstream genes, including UBE2D2, UBE2D4, BIRC3, and SLC2A4, was directly associated with the expression of cytotoxicity. In addition, PPARδ plays a pivotal role in modulating cellular susceptibility to Cd-induced renal toxicity, potentially by regulating apoptosis-related signaling pathways. In addition to apoptosis pathways, Cd toxicity through ROS generation, ferroptosis and pyroptosis were summarized. Furthermore, it has been revealed that Cd suppresses the expression of iron transport-related genes in duodenal epithelial cells leading to impaired intestinal iron absorption as well as decreased hepatic iron levels. These findings provide a mechanistic basis for Cd-induced iron deficiency anemia, implicating disrupted iron homeostasis as a contributing factor. Full article

Background: Senescence, a state of permanent cell cycle arrest, is a complex cellular phenomenon closely affiliated with age-related diseases and pathological fibrosis. Cellular senescence is now recognized as a significant contributor to organ fibrosis, largely driven by transforming growth factor beta (TGF-β) signaling, such as in metabolic dysfunction-associated steatohepatitis (MASH), idiopathic pulmonary fibrosis (IPF), chronic kidney disease (CKD), and myocardial fibrosis, which can lead to heart failure, cystic fibrosis, and fibrosis in pancreatic tumors, to name a few. MASH is a progressive inflammatory and fibrotic liver condition that has reached pandemic proportions, now considered the largest non-viral contributor to the need for liver transplantation. Methods: We previously studied Oxy210, an anti-fibrotic and anti-inflammatory, orally bioavailable, oxysterol-based drug candidate for MASH, using APOE*3-Leiden.CETP mice, a humanized hyperlipidemic mouse model that closely recapitulates the hallmarks of human MASH. In this model, treatment of mice with Oxy210 for 16 weeks caused significant amelioration of the disease, evidenced by reduced hepatic inflammation, lipid deposition, and fibrosis, atherosclerosis and adipose tissue inflammation. Results: Here we demonstrate increased hepatic expression of senescence-associated genes and senescence-associated secretory phenotype (SASP), correlated with the expression of pro-fibrotic and pro-inflammatorygenes in these mice during the development of MASH that are significantly inhibited by Oxy210. Using the HepG2 human hepatocyte cell line, we demonstrate the induced expression of senescent-associated genes and SASP by TGF-β and inhibition by Oxy210. Conclusions: These findings further support the potential therapeutic effects of Oxy210 mediated in part through inhibition of senescence-driven hepatic fibrosis and inflammation in MASH and perhaps in other senescence-associated fibrotic diseases. Full article

Barium chloride (BaCl₂), a known environmental pollutant, induces organ-specific oxidative stress through disruption of redox homeostasis. This study evaluated the protective effects and safety profile of sodium copper chlorophyllin (SCC) and ascorbic acid (ASC) against BaCl₂-induced oxidative damage in the liver and brain of mice using a two-phase experimental protocol. Animals received either SCC (40 mg/kg), ASC (160 mg/kg), or their combination for 14 days prior to BaCl₂ exposure (150 mg/L in drinking water for 7 days), allowing evaluation of both preventive and therapeutic effects. Toxicological and behavioral assessments confirmed the absence of systemic toxicity or neurobehavioral alterations following supplementation. Body weight, liver and kidney indices, and biochemical markers (Aspartate Aminotransferase (ASAT), Alanine Aminotransferase (ALAT), creatinine) remained within physiological ranges, and no anxiogenic or locomotor effects were observed. In the brain, BaCl₂ exposure significantly increased SOD (+49%), CAT (+66%), GPx (+24%), and GSH (+26%) compared to controls, reflecting a robust compensatory antioxidant response. Although lipid peroxidation (MDA) showed a non-significant increase, SCC, ASC, and their combination reduced MDA levels by 42%, 37%, and 55%, respectively. These treatments normalized antioxidant enzyme activities and GSH, indicating an effective neuroprotective effect. In contrast, the liver exhibited a different oxidative profile. BaCl₂ exposure increased MDA levels by 80% and GSH by 34%, with no activation of SOD, CAT, or GPx. Histological analysis revealed extensive hepatocellular necrosis, vacuolization, and inflammatory infiltration. SCC significantly reduced hepatic MDA by 39% and preserved tissue architecture, while ASC alone or combined with SCC exacerbated inflammation and depleted hepatic GSH by 71% and 78%, respectively, relative to BaCl₂-exposed controls. Collectively, these results highlight a differential, organ-specific response to BaCl₂-induced oxidative stress and the therapeutic potential of SCC and ASC. SCC emerged as a safer and more effective agent, particularly in hepatic protection, while both antioxidants demonstrated neuroprotective effects when used individually or in combination. Full article

Background: Acetaminophen (APAP) is a popular and safe pain reliever. Due to its widespread availability, it is commonly implicated in intentional or unintentional overdoses, which result in severe liver impairment. Pristimerin (Prist) is a natural triterpenoid that has potent antioxidant and anti-inflammatory properties. Our goal was to explore the protective effects of Prist against APAP-induced acute liver damage. Method: Mice were divided into six groups: control, Prist control, N-acetylcysteine (NAC) + APAP, APAP, and two Prist + APAP groups. Prist (0.4 and 0.8 mg/kg) was given for five days and APAP on day 5. Liver and blood samples were taken 24 h after APAP administration and submitted for different biochemical and molecular assessments. Results: Prist counteracted APAP-induced acute liver damage, as it decreased general liver dysfunction biomarkers, and attenuated APAP-induced histopathological lesions. Prist decreased oxidative stress and enforced hepatic antioxidants. Notably, Prist significantly reduced the genetic and protein expressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-II), p-phosphatidylinositol-3-kinase (p-PI3K), p-protein kinase B (p-AKT), and the inflammatory cytokines: nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α), and interleukins-(IL-6 and IL-1β) in hepatic tissues. Additionally, the m-RNA and protein levels of the apoptotic Bcl2-associated X protein (BAX) and caspase-3 were lowered and the anti-apoptotic B-cell leukemia/lymphoma 2 (BCL-2) was increased upon Prist administration. Conclusion: Prist ameliorated APAP-induced liver injury in mice via its potent anti-inflammatory/antioxidative and anti-apoptotic activities. These effects were mediated through modulation of NF-κB/iNOS/COX-II/cytokines, PI3K/AKT, and BAX/BCL-2/caspase-3 signaling pathways. Full article

(1) Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by liver damage similar to alcoholic fatty liver disease, including triglyceride infiltration of hepatocytes, regardless of alcohol consumption. It leads to progressive liver damage, such as loss of liver function, cirrhosis, and liver cancer, and the response rate of drugs under clinical research is less than 50%. There is an urgent need for biomarkers to evaluate the efficacy of these drugs. (2) Methods: MASLD was induced in mice using a High-Fat diet (HF), Western diet (WD), and Methionine/Choline-Deficient diet (MCD) for 20 weeks (4 weeks for MCD). Liver tissue biopsies were performed, and the treatment effects of saponin and non-saponin feeds were evaluated. Fat accumulation and hepatic inflammation were measured, and mRNA sequencing analysis was conducted. The therapeutic effects were validated using patient-derived liver organoids. (3) Results: The NAFLD Activity Score (NAS) significantly increased in all MASLD models compared with controls. Saponin treatment decreased NAS in the HF and WD groups but not in the MCD group. RNA sequencing and PCA analysis showed that the HF saponin response samples were similar to normal controls. DAVID analysis revealed significant changes in lipid, triglyceride, and fatty acid metabolic processes. qRT-PCR confirmed decreased fibrosis markers in the HF saponin response group, and GSEA analysis showed reduced HAMP1 gene expression. (4) Conclusions: Among the diets, red ginseng was most effective in the HF diet, with significant effects in the saponin-treated group. The therapeutic efficacy was better when HAMP1 expression was increased. Therefore, we propose HAMP1 as a potential exploratory biomarker to assess the saponin response in a preclinical setting. In addition, the reduction of inflammation and hepatic iron accumulation suggests that saponins may exert antioxidant effects through modulation of oxidative stress. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a major global health challenge characterized by complex adipose–liver interactions mediated by adipokines and hepatokines. Despite rapid field evolution, a comprehensive understanding of research trends and translational advances remains fragmented. This study systematically maps the scientific landscape through bibliometric analysis, identifying emerging domains and future clinical translation directions. Methods: A comprehensive bibliometric analysis of 1002 publications from 2004 to 2025 was performed using thematic mapping, temporal trend evaluation, and network analysis. Analysis included geographical and institutional distributions, thematic cluster identification, and research paradigm evolution assessment, focusing specifically on adipokine–hepatokine signaling mechanisms and clinical implications. Results: The United States and China are at the forefront of research output, whereas European institutions significantly contribute to mechanistic discoveries. The thematic map analysis reveals the motor/basic themes residing at the heart of the field, such as insulin resistance, fatty liver, metabolic syndrome, steatosis, fetuin-A, and other related factors that drive innovation. Basic clusters include metabolic foundations (obesity, adipose tissue, FGF21) and adipokine-centered subjects (adiponectin, leptin, NASH). New themes focus on inflammation, oxidative stress, gut microbiota, lipid metabolism, and hepatic stellate cells. Niche areas show targeted fronts such as exercise therapies, pediatric/novel adipokines (chemerin, vaspin, omentin-1), and advanced molecular processes that focus on AMPK and endoplasmic-reticulum stress. Temporal analysis shows a shift from single liver studies to whole models that include the gut microbiota, mitochondrial dysfunction, and interactions between other metabolic systems. The network analysis identifies nine major clusters: cardiovascular–metabolic links, adipokine–inflammatory pathways, hepatokine control, and new therapeutic domains such as microbiome interventions and cellular stress responses. Conclusions: In summary, this study delineates current trends and emerging areas within the field and elucidates connections between mechanistic research and clinical translation to provide guidance for future research and development in this rapidly evolving area. Full article

The global obesity epidemic and associated metabolic disorders present urgent public health challenges. This study employed a multi-omics approach (lipidomics, metabolomics, and gut microbiome analysis) to investigate how Bletilla striata polysaccharides (BSPs) and composite polysaccharides modulate liver lipid metabolism and gut microbiota in high-fat diet (HFD)-induced obese mice. HFD elevated hepatic phosphatidylcholines, cholesteryl esters (CEs), and acylcarnitines (CARs), alongside increased cecal choline and trimethylamine. BSP interventions reduced hepatic CEs, free fatty acids (FAs), CARs, and cecal sarcosine while restoring gut microbial diversity. Notably, BSP enriched beneficial genera, including Jeotgalicoccus and Atopostipes, and the network analysis revealed negative correlations between these genera and hepatic triglycerides (TGs), implicating the gut–liver axis in lipid metabolism regulation. These findings elucidate the anti-obesity mechanisms of polysaccharides through gut microbiota remodeling and cross-tissue metabolic interactions, providing a foundation for leveraging plant polysaccharides in developing safer, effective obesity therapies. Full article

Huntington’s disease (HD) is characterized by progressive neurodegeneration, but increasing evidence points to multisystemic involvement, including early hepatic steatosis in pediatric HD. Therefore, it is important to consider systemic alterations, particularly in liver lipid metabolism. In this study, we analyzed fatty acid (FA) profiles in two symptomatic HD mouse models: 2-month-old R6/2 mice representing early-onset HD and 22-month-old Hdh^Q150/Q150 (Hdh) mice representing late-onset HD, along with age-matched wild-type (WT) controls. FA composition in liver tissue was assessed by gas chromatography–mass spectrometry (GC–MS). In R6/2 mice, we observed increased levels of total iso-branched chain, monounsaturated, and n-6 polyunsaturated FAs compared to WT. In contrast, only a few FA species showed reduced concentrations in Hdh mice. Overall, our results indicate that R6/2 mice exhibit more pronounced alterations in hepatic FA profiles than Hdh mice, suggesting that early-onset HD may be associated with more severe peripheral metabolic dysregulation. Full article

Background: The metabolic dysfunction-associated steatotic liver disease (MASLD) represents an escalating global health concern, with effective treatments still lacking. Given its complex pathogenesis, multi-targeted strategies are highly desirable. Methods: This study reports the isolation of four flavone C-glycosides (FCGs) from Dianthus superbus L. and explores their potential in treating MASLD. The bioactivity and underlying mechanisms of FCGs were systematically evaluated by integrating network pharmacology, molecular docking, and zebrafish model validation. Results: Network pharmacology analysis revealed that FCGs may modulate multiple MASLD-related pathways, including lipid metabolism, insulin signaling, inflammation, and apoptosis. Molecular docking further confirmed strong binding affinities between FCGs and key protein targets involved in these pathways. In the zebrafish model of MASLD induced by egg yolk powder, FCGs administration markedly attenuated obesity, hepatic lipid accumulation, and liver tissue damage. Furthermore, FCGs improved lipid metabolism and restored locomotor function. Molecular analyses confirmed that FCGs upregulated PPARγ expression to promote lipid metabolism, restored insulin signaling by enhancing INSR, PI3K, and AKT expression, and suppressed inflammation by downregulating TNF, IL-6 and NF-κB. Additionally, FCGs inhibited hepatocyte apoptosis by elevating the BCL-2/BAX ratio. Conclusions: These findings highlight the multi-pathway regulatory effects of FCGs in MASLD, underscoring its potential as a novel therapeutic candidate for further preclinical development. Full article

Background/Objectives: Diatomaceous earth (DE), a natural substance rich in amorphous silica and recognized as a food additive, is gaining attention as a dietary silicon supplement. However, its bioavailability and impact on lipid digestion and absorption remain poorly characterized. This study aimed to investigate silicon bioavailability after short-term DE supplementation and its effects on postprandial glycemia and triglyceridemia, the expression of lipid metabolism-related proteins, and the modulation of the intestinal mucosal barrier. Methods: Female Wistar rats received daily oral supplementation of DE (equivalent to 2 or 4 mg silicon/kg body weight) for one week. Silicon digestibility, excretion, and hepatic accumulation were quantified. Postprandial glycemia and triglyceridemia were monitored. Lipid profile was analyzed by HPSEC in gastric and intestinal contents. Jejunal morphology and mucin-secreting cells were assessed histologically. Lipid metabolism markers were evaluated by immunohistochemistry and Western blot in both intestinal and hepatic tissues. Results: DE supplementation enhanced silicon absorption and increased hepatic levels. Fecal output and moisture content were also elevated, especially at the higher dose. DE significantly reduced postprandial triglyceridemia and consequently increased luminal triglyceride retention. These changes were associated with decreased jejunal levels of IFABP, ACAT2, and MTP, as well as reduced hepatic levels of MTP and LDLr, alongside increased levels of ABCG5/G8 and LXRα/β, indicating a partial blockage of lipid absorption and enhanced cholesterol efflux. The effects on the intestinal barrier were evidenced by villi shortening and an increase in mucin-producing cells. Conclusion: Food-grade DE is a bioavailable source of silicon with hypolipidemic potential, mainly by reducing intestinal lipid absorption. This is supported by lower postprandial triglycerides, increased luminal lipid retention, and decreased expression of lipid transport proteins. The study in healthy female rats underscores the importance of sex-specific responses and supports DE as a dietary strategy to improve lipid metabolism. Full article

We conducted systematic glycomic and glycoproteomic profiling to characterize the dynamic N-glycosylation landscape of rat serum, with particular focus on sex- and time-dependent variations. MALDI-TOF-MS analysis revealed that rat serum N-glycans are predominantly biantennary, disialylated complex-type structures with extensive O-acetylation of Neu5Ac residues, especially in females. LC-MS/MS-based glycoproteomic analysis of albumin/IgG-depleted serum identified 87 glycoproteins enriched in protease inhibitors (e.g., serine protease inhibitor A3K) and immune-related proteins such as complement C3. Temporal analyses revealed stable sialylation in males but pronounced daily fluctuations in females, suggesting hormonal influence. Neu5Gc-containing glycans were rare and mainly derived from residual IgG, as confirmed by glycomic analysis. In contrast to liver-derived glycoproteins, purified IgG exhibited Neu5Gc-only sialylation without O-acetylation, underscoring distinct sialylation profiles characteristic of B cell-derived glycoproteins. Region-specific glycosylation patterns were observed in IgG, with the Fab region carrying more disialylated structures than Fc. These findings highlight cell-type and sex-specific differences in sialylation patterns between hepatic and immune tissues, with implications for hormonal regulation and biomarker research. This study provides a valuable dataset on rat serum glycoproteins and underscores the distinctive glycosylation features of rats, reinforcing their utility as model organisms in glycobiology and disease research. Full article

Tebuconazole (TBZ), a triazole-class fungicide widely used in agriculture, is frequently detected in aquatic environments due to runoff and leaching, where it poses a threat to non-target aquatic organisms. This study investigates the acute toxicity of TBZ on juvenile rainbow trout (Oncorhynchus mykiss), a commercially important cold-water fish species. The 96 h LC₅₀ value was determined to be 9.05 mg/L using probit analysis. In addition to mortality, the physiological responses of fish exposed to both LC₅₀ and maximum tolerance concentration (MTC; 6 mg/L) were evaluated through haematological and histological assessments. TBZ exposure significantly suppressed key haematological parameters, particularly WBC, RBC, HGB, HCT, and LYM, indicating immunosuppression and potential hypoxia. Histological examination revealed progressive and regressive damage in gill tissues, including epithelial lifting, hyperplasia, and hypertrophy, which were more severe in the LC₅₀ group. These alterations were quantified using a semi-quantitative scoring system. Additionally, significant changes in biochemical parameters such as ALT, AST, creatinine, total protein, and glucose levels were observed, further indicating hepatic and renal dysfunctions induced by TBZ exposure. The findings demonstrate that TBZ exposure induces substantial physiological and structural impairments in rainbow trout, highlighting the importance of assessing the ecological risks of fungicide contamination in aquatic environments. The study also provides a dose–response model that can be used to estimate mortality risk in aquaculture operations exposed to TBZ. Full article

Background: Studies on ketogenic diets with a higher percentage of fat composition have revealed conflicting results regarding the modulation of lipid metabolism and tissue inflammation. Furthermore, studies on soy protein consumption in ketogenic diets remain limited. In this study, the effects of ketogenic diets on hepatic and adipose tissue inflammation and of soy protein replacement in ketogenic diets were investigated. Methods: Mice were randomly assigned to a control diet (C), ketogenic diet (KD), or ketogenic with soy protein (KS) groups for an 18-week experiment. Both ketogenic diet groups were fed a low-carbohydrate, high-fat diet during the first 12 weeks and a ketogenic diet during the last 6 weeks of the experiment. The KS group was fed the same diet as the KD group, but soy protein was substituted for casein during the last 6 weeks. Results: The KD and KS groups exhibited higher plasma β-hydroxybutyrate levels; a higher incidence of hyperlipidemia; and lower blood glucose, mesenteric fat mass, adipose tissue TNF-α, IL-1β levels, and NLRP3 protein expression compared with the C group. In the gut microbiota analysis, the KD group had a higher F-B ratio than the C group. Greater A. muciniphila abundance and a lower F-B ratio were noted in the KS group compared with the KD group. Conclusions: Although ketogenic diets decreased mesenteric fat mass and adipose tissue inflammation and modulated NLRP3 expression, they were associated with hepatic inflammation and gut dysbiosis. Soy protein consumption in a ketogenic diet did not differ from casein consumption regarding diet-induced tissue inflammation, but it may have altered the gut microbiota. Full article

Thyroid hormones (thyroxine, T₄, and triiodothyronine, T₃) are indispensable for sustaining vertebrate life, and their deficiency gives rise to a wide range of symptoms characteristic of hypothyroidism, affecting 5–10% of the world’s population. The precursor for thyroid hormone synthesis is thyroglobulin (Tg), a large iodoglycoprotein consisting of upstream regions I-II-III (responsible for synthesis of most T₄) and the C-terminal CholinEsterase-Like (ChEL) domain (responsible for synthesis of most T₃, which can also be generated extrathyroidally by T₄ deiodination). Using CRISPR/Cas9-mediated mutagenesis, we engineered a knock-in of secretory ChEL into the endogenous TG locus. Secretory ChEL acquires Golgi-type glycans and is properly delivered to the thyroid follicle lumen, where T₃ is first formed. Homozygous knock-in mice are capable of thyroidal T₃ synthesis but largely incompetent for T₄ synthesis such that T₄-to-T₃ conversion contributes little. Instead, T₃ production is regulated thyroidally by thyrotropin (TSH). Compared to cog/cog mice with conventional hypothyroidism (low serum T₄ and T₃), the body size of ChEL-knock-in mice is larger; although, these animals with profound T₄ deficiency did exhibit a marked elevation of serum TSH and a large goiter, despite normal circulating T₃ levels. ChEL knock-in mice exhibited a normal expression of hepatic markers of thyroid hormone action but impaired locomotor activities and increased anxiety-like behavior, highlighting tissue-specific differences in T₃ versus T₄ action, reflecting key considerations in patients receiving thyroid hormone replacement therapy. Full article