Hepatic Damage Research Articles

Phytochemical profile of Taxus globosa Schltdl. and its anxiolytic, antinociceptive, and toxicological evaluation in mice.

Taxus globosa Schltdl. (Taxaceae) is commonly named "Tejo mexicano". It's a Mexican plant known in folk medicine as a remedy for pain such as stomachache and headache, arthritis, gout, and other inflammatory conditions. It belongs to the Taxus genus and contains one of the most successful natural anticancer drugs, paclitaxel, among other bioactive compounds. To provide preclinical evidence of its phytochemical, toxicological, and pharmacological properties at central and peripheral levels for analgesia, as well as anxiolytic, due to its central nervous system (CNS) depressant properties. Initially, the median lethal dose (LD50) of a polar extract of T. globosa was calculated to determine the doses for evaluating anxiolytic and antinociceptive activities, where the possible participation of endogenous opioids and serotonin 5-HT1A inhibitory receptors was explored, including electrocorticographic analysis. Phytochemical screening was also included using different chromatographic techniques to compare samples from wild and cultivated sources. The acute toxicity was estimated to be greater than 316.23 mg/kg, i.p. in mice. The T. globosa extract produced a significant anxiolytic effect at 30 mg/kg, i.p., and an antinociceptive effect at a dosage of 56.2 mg/kg, i.p., mainly as anti-inflammatory, where both endogenous opioids and 5-HT1A serotonin receptors participated due to the presence of several known bioactive metabolites. No evidence of gastric, hepatic, renal, or cerebral damage was observed at therapeutic doses. Our results provide preclinical evidence for the pharmacological medicinal properties of T. globosa in producing CNS depressant activity, useful as a remedy for anxiety and pain therapy in folk medicine.

The gut microbiota-produced vitamin B6 mitigates alcohol-associated liver disease by attenuating hepatic oxidative stress damage.

Alcohol-associated liver disease (ALD) is a major clinical issue characterized by progressive stages, including hepatic steatosis, liver fibrosis, cirrhosis, and HCC. Patients with long-term chronic alcoholism often present with gut microbiota dysbiosis and reduced plasma levels of vitamin B6. This study aimed to verify that gut microbiota disruption in ALD significantly contributes to reduced in vivo production of vitamin B6 and to investigate the role of this reduction in the pathogenesis of ALD. The ALD was investigated utilizing the Gao-binge mouse model. Fecal microbial composition was analyzed in pair-fed mice and ALD mice to identify alcohol-induced functional changes in the microbiota. Additionally, liver protein expression profiles and liver and plasma metabolomic profiles were characterized to elucidate the role of vitamin B6 in ALD pathogenesis through integrated proteomic and metabolomic analyses. The findings were further validated using animal models and clinical patient samples. Alcohol consumption disrupted the gut microbiota in the mice, impairing the vitamin B6 synthesis by intestinal microorganisms. Vitamin B6 deficiency aggravated the disorder of amino acid metabolism in the liver and inhibited ornithine aminotransferase expression, thereby worsening oxidative stress damage. In patients with ALD, significant disturbances of gut microbiota were observed, along with decreased intestinal vitamin B6 levels, which were negatively correlated with serum biochemical markers. The imbalance of gut microbiota in ALD mice reduces vitamin B6 synthesis, which affects amino acid metabolism and glutathione synthesis in the liver, thereby exacerbating ALD. These findings suggest that vitamin B6 may play a critical protective role in ALD progression by regulating amino acid metabolism.

Ameliorative activity of cinnamon extract (Cinnamomum Cassia) against aluminum oxide nanoparticle (Al2O3 NP) induced hepatic damage

Ameliorative activity of cinnamon extract (Cinnamomum Cassia) against aluminum oxide nanoparticle (Al2O3 NP) induced hepatic damage

Type 2 Diabetes Mellitus in Inflammatory Bowel Disease Patients: A Case-Control Study Through a Long Follow-Up Period.

Background/Objectives: The characterization of patients with inflammatory bowel disease (IBD) and type 2 diabetes mellitus (T2DM) as a new group has not been well detailed. This study aimed to evaluate the impact of T2DM on IBD progression and analyze the prevalence of steatotic liver disease and liver damage in these patients. Methods: Through a retrospective case-control study, we compared severe IBD occurrence in patients with both IBD-T2DM (cases) versus those with IBD alone (controls). Among 1047 medical records, 79 IBD-T2DM patients were selected and compared to 308 controls in a 1:4 ratio. Severe IBD was defined by variables such as surgery, target therapy, corticosteroid use, and hospitalization. Liver damage was assessed using Fib-4 (>1.3), and hepatic steatosis was evaluated by imaging. Results: There was no significant difference in severe disease rates (59.5% vs. 59.7%; p = 0.97). IBD-T2DM patients had higher rates of hepatic steatosis (62.9% vs. 27.2%; p < 0.0001) and liver damage (55.4% vs. 26.6%; p < 0.0001). IBD-T2DM patients used more corticosteroids (p < 0.0001) and fewer anti-TNF-alpha drugs (p = 0.007). The median age at diagnosis was higher in IBD-T2DM patients (48 vs. 32; p < 0.0001). In Crohn's disease, 24.3% of IBD-T2DM patients had exclusive colonic involvement compared to 5% in the IBD-only group (p = 0.003). Conclusions: T2DM was not associated with worse IBD progression, but was linked to increased liver steatosis and damage. Differences such as age of onset, colonic involvement, and liver damage suggest that IBD-T2DM patients could configure a special population worthy of further studies.

Evaluation of the Hepato and Reno protective Effects of Methanol Seed Extract of Unripe Carica papaya (pawpaw) Seed in Wistar Rats Exposed to Carbon tetrachloride (CCl4)

Rapid urbanization leads to high rates of organ failure due to toxic industrial emissions. This necessitates the need to develop solutions from natural materials, with the perceived potential to protect vital organs against the damaging effects of these emissions that can be easily transformed into beverages. This study evaluated the hepato and reno-protective effects of methanol seed extract of unripe Carica papaya (pawpaw). Twenty-five adult male Wistar rats were divided into five groups of five rats each. Group I served as the normal control and received 2 ml of distilled water. Group II was the negative control (administered CCl4 only). Groups III-V were administered 200, 400, and 600 mg/kg of methanol seed extract of unripe fruit before induction of renal and hepatic damage with carbon tetrachloride (CCl4). The extract was administered to animals for 28 days, after which the animals were euthanized, and samples were collected in appropriately labeled containers. Evaluation of serum markers of hepatic and renal injury was performed using standard procedures. Both serum hepatic and renal markers alkaline phosphatase (ALP), alanine transaminase (ALT), aspartate aminotransferase (AST), creatinine, and urea) were elevated in the negative control group beyond the levels reported for the normal control. However, a contrary observation was made in urea, creatinine, Na+, K+, Cl-, HCO3, and ALT, AST, and ALP, respectively. In conclusion, it can be inferred from the results of this study that methanol extract of unripe pawpaw seed has the potential to protect against hepatic and renal damage.

Augmenting the safety and therapeutic efficacy of doxycycline and rifampicin-loaded solid lipid nanoparticles against Brucella abortus using murine model

Abstract Background Prolonged therapy, hepatic damage, and the development of drug resistance are the limitations of doxycycline and rifampicin in the treatment of brucellosis. This study was designed to assess the effect of solid lipid nanoparticles (SLNs) encapsulation of these antimicrobials against brucella. SLNs were prepared by a double emulsion method and characterized for entrapment efficiency, particle size distribution, drug release, infrared spectroscopy, differential scanning calorimetry, and scanning electron microscopy. The encapsulated formulations were tested for stability, safety, and in vitro antimicrobial assay on brucella and brucella-infected mice models. Results The particle size, polydispersity index and zeta potential of doxycycline encapsulated SLN size were 443.6 ± 3.03 nm, 0.858 ± 0.00, and + 26.5 ± 1.87 mV, respectively. The rifampicin SLN showed particle size, polydispersity index, and zeta potential of 348.7 ± 3.35 nm, 0.234 ± 0.00, and + 22.9 ± 1.59 mV. The entrapment efficiency of doxycycline and rifampicin encapsulated SLN was 98% and 96%, respectively. The drug-loaded SLN retained the biophysical properties, drug loading, and entrapment efficiency after storage at 4 °C as well as 25 °C for 6 months. The Fourier transform infrared spectroscopy depicted effective encapsulation and the Differential scanning colorimetry thermogram revealed a negative interaction of drug and polymer. Drug release parameters were fitted well with the Korsmeyer–Peppas and Hixson–Crowell model (R2 ≥ .09). The MIC findings showed a reduction in MIC values of SLN-encapsulated rifampicin; whereas, doxycycline did not show any changes. The MBC value for free and SLN-encapsulated doxycycline and rifampicin did not show changes. SLN encapsulation did not show any cytotoxicity on murine macrophage cell line RAW 264.76 for both drugs. Doxycycline and rifampicin significantly reduced the CFU of B. abortus compared to the free drug (P &gt; 0.05), resulting in less damage to the liver and kidneys. Conclusions The present study concludes that SLN encapsulation of doxycycline and rifampicin would be safe and effective for the prolonged treatment regimen against Brucella infection. Graphical abstract

Short-chain fatty acids as a novel intervention for high-fat diet-induced metabolic syndrome.

Metabolic syndrome (MetS) is driven by a complex interplay of genetic, lifestyle, and dietary factors, leading to weight gain, insulin resistance, dyslipidemia, and chronic inflammation. Gut microbiota dysbiosis has been recently recognized as a key contributor to MetS, leading to advancements in gut microbiome-based interventions to improve health outcomes. Considering the unique challenges associated with the use of pre/probiotics, short-chain fatty acids (SCFA), also known as postbiotics, have emerged as promising therapeutic agents due to their role in modulating host metabolism and physiology. Considering this, the aim of the current study was to explore the therapeutic potential of SCFA (butyrate, propionate, and acetate) supplementation against a high-fat diet (HFD)-induced experimental model of MetS in male Wistar rats. Alterations in body weight, lipid profile, histopathology, and adipose tissue accumulation were assessed to establish SCFA-mediated amelioration of experimental MetS. Further, the enzymatic (GPx, Catalase, GR, and GST) and non-enzymatic (LPO, total ROS, and Redox ratio were evaluated. The results indicated that SCFA supplementation could effectively mitigate key features of MetS. A significant reduction in body weight gain and fasting blood glucose levels, along with markedly lowered triglycerides, total cholesterol, and LDL levels, with partial restoration of HDL levels was observed following SCFA supplementation. SCFA administration also attenuated MetS-associated hepatic damage as studied by histopathological investigation and analysis of liver function marker enzyme activities. Such ameliorative effects of SCFA against HFD-induced MetS were owed to potential redox modulation studied using enzymatic and non-enzymatic oxidative stress markers. In conclusion, the study's outcomes show that SCFA supplementation could potentially be used against managing MetS. It underscores the therapeutic potential of SCFA by placing them as a novel gut microbiome-based dietary approach to improve metabolic health and reduce the risk of MetS-associated complications. However, more detailed mechanistic explorations are warranted in the future, leading to their beneficial role in MetS contributing to holistic health outcomes.

Rice Straw-Derived Biochar Mitigates Microcystin-LR-Induced Hepatic Histopathological Injury and Oxidative Damage in Male Zebrafish via the Nrf2 Signaling Pathway.

Microcystin-leucine arginine (MC-LR) poses a serious threat to aquatic animals during cyanobacterial blooms. Recently, biochar (BC), derived from rice straw, has emerged as a potent adsorbent for eliminating hazardous contaminants from water. To assess the joint hepatotoxic effects of environmentally relevant concentrations of MC-LR and BC on fish, male adult zebrafish (Danio rerio) were sub-chronically co-exposed to varying concentrations of MC-LR (0, 1, 5, and 25 μg/L) and BC (0 and 100 μg/L) in a fully factorial experiment. After 30 days exposure, our findings suggested that the existence of BC significantly decreased MC-LR bioavailability in liver. Furthermore, histopathological analysis revealed that BC mitigated MC-LR-induced hepatic lesions, which were characterized by mild damage, such as vacuolization, pyknotic nuclei, and swollen mitochondria. Compared to the groups exposed solely to MC-LR, decreased malondialdehyde (MDA) and increased catalase (CAT) and superoxide dismutase (SOD) were noticed in the mixture groups. Concurrently, significant changes in the mRNA expression levels of Nrf2 pathway genes (cat, sod1, gstr, keap1a, nrf2a, and gclc) further proved that BC reduces the oxidative damage induced by MC-LR. These findings demonstrate that BC decreases MC-LR bioavailability in the liver, thereby alleviating MC-LR-induced hepatotoxicity through the Nrf2 signaling pathway in zebrafish. Our results also imply that BC could serve as a potentially environmentally friendly material for mitigating the detrimental effects of MC-LR on fish.

Rol de la alteración del eje microbiota-intestino-hígado en la enfermedad hepática esteatósica asociada a disfunción metabólica

Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the leading causes of liver morbidity worldwide, including conditions such as hepatocellular carcinoma and the need for liver transplantation, with a particularly high prevalence in Latin America. The pathogenesis of MASLD is multifactorial, involving both genetic and environmental factors, including dysfunction of the gut-liver axis. The mechanisms involved in the progression of liver disease to cirrhosis are not yet fully understood. Recently, the intestinal microbiota has been recognized as playing a crucial role in disease progression by modulating systemic and hepatic inflammatory responses. In MASLD patients, microbial dysbiosis contributes to intestinal barrier dysfunction, increasing intestinal permeability and facilitating the translocation of microbial products to the liver, thereby exacerbating inflammation and hepatic damage. Additionally, alterations in bile acid levels and microbial metabolites further reinforce this pathological cycle. Therapeutic strategies aimed at restoring microbial balance—such as fecal microbiota transplantation, probiotics, prebiotics, and synbiotics—have shown promising results in modulating the microbiota-gut-liver axis and slowing MASLD progression. Further studies are needed to fully understand their impact on the pathophysiology of MASLD and to strengthen their integration into current therapeutic protocols for this disease.

Alpha1-adrenergic receptor blocking action of carvedilol contributes to tackling dexamethasone-induced insulin resistance and to a lesser extent hepatic damage

Alpha1-adrenergic receptor blocking action of carvedilol contributes to tackling dexamethasone-induced insulin resistance and to a lesser extent hepatic damage

Metformin ameliorates diabetes-induced hepatic ultrastructural damage and the immune biomarker CD86 and inflammation in rats

ABSTRACT Diabetes is a known inducer of hepatic ultrastructural alterations, and the expression of the immune biomarker that involves in T-cell immunity, cluster of differentiation 86 (CD86) is increased in diabetic patients with liver cirrhosis. The antidiabetic drug metformin has not previously been used to protect against type 2 diabetes mellitus (T2DM)-induced alternations in hepatic ultrastructure and the induction of the hepatic CD86/inflammation axis in diabetic animal models induced by streptozotocin and a high fat diet. To test our hypotheses, T2DM was induced in rats (model group) and the protective animals were treated with the antidiabetic drug metformin (200 mg/kg) until being sacrificed at week 12. A profound ultrastructural damage to the hepatocytes and liver tissue injury was induced by T2DM as demonstrated by hepatocytes with dark shrunken irregular nuclei, rarefied cytoplasm with lipid droplets, mitochondria with disrupted cristae, as well as depletion of glycogen granules and damaged of liver architecture, which were effectively (p < .0001) protected with metformin. Metformin also suppressed diabetes-induced hepatic gene expression of CD86 and inflammation as well as glycemia and liver injury markers. Furthermore, a significant correlation between hepatocyte damage and CD86, inflammation, glycemia, and biomarkers of liver injury was observed. These findings demonstrate that diabetes is associated with the induction of the hepatic CD86/inflammation axis and hepatocyte ultrastructural alterations while being protected by metformin.

End-organ protective effect of serelaxin in patients hospitalized for heart failure: Results of the biomarker substudy of Relaxin in Acute Heart Failure-2 (RELAX-AHF-2).

Serelaxin is recombinant human relaxin-2, a hormone responsible for haemodynamic adaptations and organ protection in pregnancy. In the RELAX-AHF trial, serelaxin demonstrated reductions in cardiac, renal and hepatic damage. In RELAX-AHF-2, organ damage-related biomarkers were assessed in a biomarker substudy. Patients enrolled within 16 h of presentation for heart failure hospitalization were randomized to 48-h infusions of either serelaxin (30 μg/kg/day) or placebo, and plasma samples were obtained at baseline, 2, 5, and 14 days in patients participating in the biomarker substudy. Of the 6545 patients analysed in RELAX-AHF-2, 1020 (15.6%) patients (mean age 72 ± 12 years; 61% male) were enrolled in the biomarker substudy. Compared to placebo, serelaxin decreased percentage change from baseline in troponin T through day 14 (serelaxin +0.2% vs. placebo +40.3%; p = 0.042), as well as creatinine (-0.8% vs. +5.8%; p = 0.002), cystatin C (+3.8% vs. +8.3%; p = 0.016), and uric acid (+0.8% vs. +7.2%; p = 0.0014) at day 2. The decrease of N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to day 2 was greater in serelaxin-treated patients (-39.8% vs. -27.6%; p = 0.002). Early changes in NT-proBNP and troponin, but not creatinine, cystatin C and uric acid, were associated with 180-day mortality. In this substudy population, serelaxin did not reduce 180-day cardiovascular death (hazard ratio [HR] 0.78; 95% confidence interval [CI] 0.49-1.25; p = 0.30), but significantly reduced worsening heart failure through day 5 (HR 0.55; 95% CI 0.33-0.93; p = 0.027). In this substudy, serelaxin decreased plasma concentrations of cardiac, renal and hepatic injury markers. Changes of most of these markers were associated with cardiovascular mortality. In this pre-specified biomarker subgroup, serelaxin did not reduce 180-day cardiovascular mortality but significantly reduced worsening heart failure through day 5.

Effect of glucose selenol on hepatic lipid metabolism disorder induced by heavy metal cadmium in male rats.

This study used 24 male rats to determine the protective effects of a new selenium molecule (glucose selenol) on cadmium (Cd) induced hepatic toxicity. The rats were randomly divided into four groups: control group, Cd group, Cd + 0.15 Se group, and Cd + 0.4 Se group. The results showed that glucose selenol supplementation alleviated the adverse impact of Cd on lipid metabolism, including decreased serum triacylglycerol and cholesterol levels. Transcriptome analysis revealed that, compared to the control group, Cd changed the expression of 1379 genes - discernibly affecting lipid metabolism pathways. Proteomic analysis primarily indicated alterations in lipid metabolism-related pathways. In conclusion, glucose selenol restored lipid metabolism disorders induced by Cd, thus rescuing hepatic damage. This integrated analysis identified the influence of glucose selenol on Cd-induced hepatic toxicity and provided its potential application prospects in alleviating the impact of heavy metal pollution, such as Cd, on human health.

Long-Term Yo-Yo Dieting Exaggerates Liver Steatosis and Lesions but Preserves Muscle Performance in Male Zebrafish.

Weight regain within one year after weight loss is frequently observed and is referred to as yo-yo dieting or weight cycling. In this study, we explore the effects of yo-yo dieting on the liver, adipose tissue, and muscle characteristics of male zebrafish. Four-month-old AB wild-type male zebrafish were randomly assigned to three groups: high-calorie intake (H, seven meals per day), low-calorie intake (L, two meals per day), and yo-yo diet (the low- and high-calorie alternation switched every two weeks) groups. Feeding the fish the H diet for over 8 weeks led to steatosis and damage to the liver. The yo-yo diet reduced liver lipid accumulation at week eight but caused a similar degree of lipid accumulation as the H diet thereafter. It was found that twenty weeks of yo-yo dieting actually exacerbated hepatic damage. Compared to the L diet, feeding the fish on the yo-yo and H diets for a period of 20 weeks significantly increased the size of muscle fibers, resulting in higher speed during burst swimming and a significant increase in the size and number of adipocytes in the abdominal tissue. To summarize, short-term yo-yo dieting was found to attenuate hepatosteatosis and maintain fast-twitch muscle function. Long-term yo-yo dieting preserved fast-twitch muscle function and muscle fiber size; however, it exacerbated the pathological changes in the liver.

Modulatory effects of CNNM4 on protein- l -isoaspartyl- O -methyltransferase repair function during alcohol-induced hepatic damage.

Alcohol-associated liver disease (ALD) is a leading cause of liver-related mortality worldwide, with limited treatment options beyond abstinence and liver transplantation. Chronic alcohol consumption has been linked to magnesium (Mg 2+ ) deficiency, which can influence liver disease progression. The mechanisms underlying Mg 2+ homeostasis dysregulation in ALD remain elusive. This study aimed to investigate the role of the Mg 2+ transporter Cyclin M4 (CNNM4) in ALD by analyzing its expression patterns in patients with ALD and preclinical animal models. In this study, CNNM4 is upregulated in the liver of both patients with ALD and animal models. CNNM4 overexpression triggers Mg 2+ homeostasis dysregulation, linked to ALD progression. We propose a novel therapeutic approach for ALD treatment using N -acetylgalactosamine silencing RNA technology to specifically modulate Cnnm4 expression in the liver, improving mitochondrial function and alleviating endoplasmic reticulum stress. Notably, silencing Cnnm4 restores protein isoaspartyl methyltransferase (PCMT1) activity, essential for repairing ethanol-induced protein damage. Enhancing mitochondrial activity through Cnnm4-dependent mechanisms increases S -adenosylmethionine levels, crucial for PCMT1 function, highlighting the interconnected roles of mitochondrial health and protein homeostasis in ALD treatment. These findings shed light on the dysregulation of Mg 2+ homeostasis in ALD, providing a promising therapeutic approach targeting CNNM4. N -acetylgalactosamine si Cnnm4 therapy boosts the repair processes of ethanol-damaged proteins through the upregulation of PCMT1 activity.

DINCH Exposure Triggers Inflammatory, Oxidative, and Apoptotic Pathways in the Liver of Long-Evans Lactating Rats and Their Offspring.

1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH) is a non-phthalate plasticizer used as a replacement of di(2-ethylhexyl) phthalate (DEHP) in daily usage items. It is not known whether continuous exposure to low doses of DINCH can lead to hepatic alterations, the liver being the organ responsible for its metabolism. The aim of this study was to evaluate the activation of inflammatory and apoptotic pathways in the liver of lactating dams after DINCH exposure, and whether these effects may be observed on postnatal day 6 (PND6) offspring. Two doses of DINCH were tested by oral administration to the following three groups of Long-Evans rats: control, DINCH-lower dose (LDINCH, 30 mg/kg b.w./day), and DINCH-high dose (HDINCH, 300 mg/kg b.w./day). Inflammatory mediators (IL-1β, TNF-α, NF-κB), mitochondrial transcriptional factors (PPARγ and PGC-1α), oxidative stress markers (SOD, CAT, GSSG/GSH), and components of the mitochondrial apoptotic pathway (PUMA, BAX, BAD, Bcl-2, Bcl-xL, Cytochrome c, APAF-1, Caspase-3, AIF) were assessed by the gene and protein expression in the liver of lactating dams and offspring. Exposure to LDINCH promoted the release of pro-inflammatory cytokines such as IL-1β and TNF-α and raised oxidative stress levels (GSSG/GSH), as well as increased Caspase-3 levels and reduced anti-apoptotic proteins (Bcl-2 and Bcl-xL), both in lactating dams and PND6 offspring. Thus, constant exposure to lower doses of DINCH can disrupt inflammatory and oxidant/antioxidant homeostasis, leading to hepatic tissue damage in lactating dams and having a perinatal effect in PND6 offspring.

Could chronic opioid use be an additional risk of hepatic damage in patients with previous liver diseases, and what is the role of microbiome?

Among illicit drugs, addiction from opioids and synthetic opioids is soaring in an unparalleled manner with its unacceptable amount of deaths. Apart from these extreme consequences, the liver toxicity is another important aspect that should be highlighted. Accordingly, the chronic use of these substances, of which fentanyl is the most frequently consumed, represents an additional risk of liver damage in patients with underlying chronic liver disease. These observations are drawn from various preclinical and clinical studies present in literature. Several downstream molecular events have been proposed, but recent pieces of research strengthen the hypothesis that dysbiosis of the gut microbiota is a solid mechanism inducing and worsening liver damage by both alcohol and illicit drugs. In this scenario, the gut flora modification ascribed to non-alcoholic fatty liver disease performs an additive role. Interestingly enough, HBV and HCV infections impact gut-liver axis. In the end, the authors tried to solicit the attention of operators on this major healthcare problem.

Protective effects of nutrients and antioxidant-rich seed oil and sprouted seed oil of Benincasa hispida against formaldehyde-induced hepatic and renal damage

IntroductionIn traditional Chinese medicine (TCM), Benincasa hispida, commonly referred to as wax gourd, winter melon, or ash gourd, has been used extensively for managing fever, urinary dysfunction, cough with viscous mucus, pulmonary and periappendicular abscesses, edema, spermatorrhea, gonorrhea, discharge pus, and expel dampness. In this study, we investigated the antioxidant, macro- and micronutrients as well as the protective effects of Benincasa hispida seed oil (BHSO) and sprouted seed oil (BHSSO) against formaldehyde (FA)-induced liver and kidney damage in mice. MethodsThe in vitro antioxidant activity was evaluated using the DPPH radical scavenging assay. Protein, fat, fiber, and total carbohydrate contents were assessed, and micronutrients were determined using flame atomic absorption spectrophotometry. BHSO, BHSSO, and Vitamin E (3485 mg/kg, 3485 mg/kg, and 30 mg/kg p.o., respectively) were administered once daily shortly after formaldehyde exposure (10 mg/kg, I.P.) to separate groups of Swiss albino male mice for a period of 26 days to investigate their protective effects against hepatic and renal damage. The normal control group was given access to sterile tap water and a balanced diet, whereas the disease control group was given only 10 mg/kg of formaldehyde intraperitoneally. Results and discussionSerum ALT, AST, and creatinine levels were significantly elevated after formaldehyde (FA) administration. Histopathological examinations of liver and kidney tissue revealed degenerative changes in both organs. However, mice pretreated with BHSO and BHSSO showed a significant reduction in FA-induced elevations of serum ALT, AST, and creatinine levels and retained normal liver and kidney tissue histology. BHSO and BHSSO exhibited the ability to scavenge free radicals, as shown in vitro antioxidant studies. Essential micronutrients like zinc (Zn), copper (Cu), calcium (Ca), and chromium (Cr) were also found in both oils. These micronutrients may prevent the inactivation of antioxidant enzymes, thereby increasing free radical scavenging and preserving oxidation and antioxidant equilibrium. Moreover, both oils were found to contain crude fat and carbohydrates that are essential in safeguarding against formaldehyde-induced hepatic and renal damage by offering structural and metabolic support to cells and preserving membrane integrity. ConclusionBenincasa hispida seed oil and sprouted seed oil have significant protective effects against formaldehyde-induced hepatic and renal damage and serve as a valuable source of antioxidants, as well as macro- and micronutrients.

Effects of dechlorane plus on hepatic pathology, metabolic health and gut microbiota in male mice.

Dechlorane plus (DP), a widely used flame retardant, was added to Annex A of the Stockholm Convention on Persistent Organic Pollutants in 2023. This study aimed to investigate the effects of DP on glucose and lipid metabolism by orally exposing eight-week-old male mice to environmentally relevant concentrations of DP (0.5, 1, and 5mg/kg/day) for six weeks. The in vivo effects of DP on liver histomorphology, glucose and lipid metabolism, intestinal microbiota, and the associated molecular mechanisms were assessed. Pathological examination revealed that exposure to 1 and 5mg/kg/day DP induced hepatic damage, characterized by structural disarray of the hepatic cords and vacuolar degeneration of liver cells, while 0.5 and 1mg/kg/day DP exposure led to significant triglycerides (TG) accumulation in the liver. Metabolite analysis showed a marked increase in hepatic pyruvate, glycogen, and TG in mice exposed to 0.5 and 1mg/kg/day DP, while 5mg/kg/day exposure resulted in elevated glycogen levels and reduced pyruvate and glucose concentrations. The underlying mechanisms involved the transcriptional regulation of key enzymes related to glucose and lipid metabolism, as well as the activation of the PI3K/AKT pathway. Exposure to 5mg/kg/day DP upregulated genes associated with glycogenesis (GK), glycolysis (HK1 and PK), and fatty acid synthesis (SREBP1, FAS, and ACC1), while downregulating genes involved in gluconeogenesis (PCK1) and fatty acid β-oxidation (CPT1 and PPARA). The activated PI3K/AKT pathway regulated key proteins (GLUT4, GSK3β, and FoxO1), playing distinct roles in glucose and lipid metabolism. High-throughput 16S rDNA sequencing revealed that 5mg/kg/day DP exposure altered the composition and diversity of intestinal microbiota, reducing the relative abundance of beneficial probiotics at both the phylum and genus levels. These findings offer new insights into the complex mechanisms through which DP affects glucose and lipid metabolism in mammals, contributing to a more comprehensive evaluation of its toxicity.

Interspecies transcriptome profiles of human T cell activation and liver inflammation in a xenogeneic graft-versus-host disease model

BackgroundXenogeneic transplantation induces acute graft-versus-host disease (aGvHD) and subsequent vital organ damage. Herein, we aimed to examine hepatic damage associated with aGvHD using histopathology and gene expression profiles. MethodsA xenografic GvHD model was established by engrafting human peripheral blood mononuclear cells (PBMCs) into immunodeficient NOD-scid IL2Rγnull (NSG) mice after busulfan conditioning. NSG mice were assigned to groups treated with saline (S group) or a combination of busulfan and PBMCs (BP group). Histological lesions and RNA sequencing analysis of gene profiles in the BP group (GvHD model) were compared with those in the P group. ResultsPredominant T cell subsets (95 %) in the blood of the BP group were identified as cytotoxic CD8+ T cells (56 %) and helper CD4+ T cells (31 %). Symptoms of aGvHD, including hepatocyte necrosis, bile duct hyperplasia, and human T cell infiltration, were observed. Gene expression analysis revealed upregulation of Th1 and Th2 cell differentiation (STAT4, IL4R, and NFACT1), T cell receptor signaling pathway (CD226 and GBP1), IL-1 pathway (CCL3, NAIP, and IRAK4), cell cycle (CDCA5, CDCA8, MCM5, KNL1, BUB1B, FBXO5, and CENPE) in human cells. In mouse cells, Il1a, Ifngr, Tnfrsf, and Il6ra genes (cytokines or their receptors) and Icam, Vcam, and Endra genes (adhesion molecules) were upregulated, whereas genes related to chromosome condensation (H2ac and H2bc) and fatty acid/steroid metabolism (Fasn, Rdh, and Scd) were downregulated. Interspecies gene network analysis revealed that activated human T cells are associated with liver damage through inflammatory and metabolic pathways, accompanied by increased mouse cell adhesion molecules and cytokines. ConclusionOur findings offer valuable insights into the pathophysiology and biomarkers of aGvHD and may contribute to the development of novel therapeutics.