Histological Changes In Liver Research Articles

Effect of cofactors on NAFLD/NASH and MAFLD. A paradigm illustrating the pathomechanics of organ dysfunction.

Primary nonalcoholic fatty liver disease (NAFLD) is bi-directionally associated with the metabolic syndrome and its constitutive features (“factors”: impaired glucose disposal, visceral obesity, arterial hypertension, and dyslipidemia). Secondary NAFLD occurs due to endocrinologic disturbances or other cofactors. This nosography tends to be outdated by the novel definition of metabolic associated fatty liver disease (MAFLD). Irrespective of nomenclature, this condition exhibits a remarkable pathogenic heterogeneity with unpredictable clinical outcomes which are heavily influenced by liver histology changes. Genetics and epigenetics, lifestyle habits [including diet and physical (in)activity] and immunity/infection appear to be major cofactors that modulate NAFLD/MAFLD outcomes, including organ dysfunction owing to liver cirrhosis and hepatocellular carcinoma, type 2 diabetes, chronic kidney disease, heart failure, and sarcopenia. The identification of cofactors for organ dysfunction that may help understand disease heterogeneity and reliably support inherently personalized medicine approaches is a research priority, thus paving the way for innovative treatment strategies.

Long-term surveillance of liver histological changes in chronic hepatitis C patients completing pegylated interferon-α plus ribavirin therapy: an observational cohort study.

Background:For chronic hepatitis C (CHC) patients completing pegylated interferon (PegIFN)-α/ribavirin therapy, long-term liver histological changes remain largely unexplored.Methods:This observational cohort study included 85 CHC patients completing PegIFN-α/ribavirin therapy with liver biopsies performed at baseline and the end of surveillance (EOS). Median years between paired biopsies were 6.75 (interquartile range: 5.63–7.54).Results:In patients with baseline METAVIR fibrosis stages (F) <4 (able to undergo fibrosis progression; n = 77), cases achieving sustained virological response (SVR) (n = 52) had a significantly lower rate of fibrosis progression than non-SVR cases (n = 25) (3.8% versus 24.0%, p = 0.012). Among the entire cohort (n = 85), the rate of activity response [METAVIR activity grades (A) decreasing or maintaining at A0] in SVR cases (n = 59) was significantly higher than that in non-SVR cases (n = 26) (94.9% versus 65.4%, p = 0.001). For SVR cases among the entire cohort, independent predictors of fibrosis clearance included baseline F <2 [odds ratio (OR) = 7.877, p = 0.042] and aspartate transaminase (AST) levels declining by >70% at EOS compared with baseline (OR = 9.013, p = 0.038). For non-SVR cases among the entire cohort, baseline AST levels >80 U/l and glucose levels ⩽ 105 mg/dl independently predicted significant fibrosis (F2/F3/F4) at EOS (OR = 12.558, p = 0.049) and activity response (OR = 17.741, p = 0.047), respectively.Conclusions:Among CHC patients completing PegIFN-α/ribavirin therapy, SVR lowers the risk of liver histological progression but does not guarantee fibrosis clearance. For SVR cases, those with baseline F ⩾ 2 or without significantly declined follow-up AST levels should be specifically monitored. As for non-SVR cases, those with a higher baseline AST or glucose level should preferentially receive retreatment.

Effect of various level of 5F-cumyl-pica orally gavaged to wistar rats

This research studied 5F-CUMYL-effects PICAs on white Wistar rats’ liver, kidney, and heart, as well as their biological and hematological parameters. 24 male albino rats were given orally for 14 days. Group 1 was the control; groups 2 and 3 received 5 and 50 mg/kg (bw) 5F-CUMYL-PICA. Liver and kidneys deteriorated in treated rats. Liver histological changes included inflammatory cell aggregation, cytoplasmic degeneration, karyolysis, venous congestion, hemorrhage, and edema, and steatosis degeneration. Renal tissue revealed tubule degradation and casts. Glomeruli atrophy and Bowman's space expand. Heart tissue and cardiac muscle fibers exhibited myocardial fiber degradation and inflammatory cell aggregation. Serum AST, ALT, ALP, CK, total protein, Albumin, Triglyceride, Total Bilirubin, Direct Bilirubin, Urea, Creatinine, HGB, RBC, HCT, and MCHC levels changed. According to this research, synthetic cannabis’ (5F-CUMYL-PICA) negative effects are worse on the liver and kidneys in group 3 than group 2.

The Protective Effects of Trans-Anethole against Polycystic Ovary Syndrome Induced Histopathological and Metabolic Changes in Rat.

BackgroundAim of the study was to evaluate the protective effects of trans-anethole, against polycystic ovary syn- drome (PCOS) induced histopathological and biochemical changes in female Wister rats.Materials and MethodsIn this experimental study, forty-eight animals were randomly assigned into 6 groups: con- trol; PCOS; PCOS+trans-anethole (20, 40, 80 mg/kg); and PCOS+metformin (300 mg/kg). Testosterone (1 mg/kg/ day) was injected intraperitoneally for 35 days to induce PCOS. After PCOS induction, animals were treated by trans- anethole and metformin (30 days oral gavage). Finally, serum oxidative stress and insulin levels as well as histological changes in ovaries, kidneys and liver were evaluated.ResultsIn PCOS group, the serum level of malondialdehyde (MDA) was 1.391 ± 0.18 mmol/L and significantly increased (P=0.000) compared to the control group with the MDA level of 0.35 ± 0.08. Meanwhile the activity of superoxide dismutase (SOD) and catalase (CAT), and total thiol levels were significantly decreased (P=0.000 for all groups), compared to the control group. In the trans-anethole (80 mg/kg) treated group, insulin (P=0.000) and MDA (P=0.000) levels were significantly decreased while total thiol (P=0.001) and activity of SOD (P=0.000) and CAT (P=0.007) were significantly increased compared to the PCOS group. In the metformin treated group the insulin level (P=0.03) decreased compared to the PCOS group. Histological evaluation showed multiple cysts in the ovarian tissue, an increase in inflammatory cells in the liver, and a loss of order in the structure of the tubules and glomeruli of the kidney in the PCOS group. Tissue damage was reduced in the trans-anethole treated group.ConclusionTarns-anethole at a dose of 80 mg/kg improved metabolic status, oxidative stress, liver and kidney dam- age as well as the cystic mass of ovarian tissue. To understand the exact protective effects of trans-anethole in PCOS, more experimental or clinical studies are suggested.

Hepatoprotective and Antioxidant Activity of Phoenix pusilla Fruits Extract Against Paracetamol Induced Hepatotoxicity in Freshwater Fish Cirrhinus cirrhosus

Liver damage has recently emerged as one of the biggest issues in aquaculture; many farms are experiencing the "liver syndrome," which manifests as liver enlargement (up to two to three times its original size) and colour changes. One of the main causes of the disorders may be xenobiotic challenge brought on by drug addiction and environmental contamination. There are very few effective medications that can protect the liver from harm and/or aid in the regeneration of hepatic cells, despite the enormous breakthroughs in contemporary medicine. In the current investigation, fish Cirrhinus cirrhosus with paracetamol-induced hepatotoxicity were supplemented with Phoenix pusilla fruit extract. Its hepatoprotective efficacy was proven by the restoration of the liver indicators ALT, AST, protein, and histological changes. Phoenix pusilla fruit contains a large number of secondary metabolites, such as flavonoids, which may act in a number of different ways to shield the hepatocytes from harmful chemicals. Thus, the current study concluded that Phoenix pusilla fruit may effectively prevent liver damage from paracetamol by protecting it from oxidative damage and tissue-damaging enzyme activities.

Resveratrol and its nanocrystals: A promising approach for cancer therapy?

There has been a significant research interest in nanocrystals as a promising technology for improving the therapeutic efficacy of poorly water-soluble drugs, such as resveratrol. Little is known about the interaction of nanocrystals with biological tissue. The aim of this study was to investigate the potential use of resveratrol (RSV) and its nanocrystals (NANO-RSV) as antitumor agents in Ehrlich ascites tumour (EAT)-bearing mice and the interaction of nanocrystals with biological tissue through biochemical and histological changes of kidney, liver and EAT cells. After intraperitoneal injection of 2.5 × 106 cells into the abdominal cavity of mice, treatment of animals was started next day by injecting RSV or NANO-RSV at a dose of either 25 or 50 mg/kg every other day for 14 days. The results show that the administration of resveratrol and its nanocrystals lead to significant reductions in the proliferation of tumour cells in the abdominal cavity, and a reduction of the number of blood vessels in the peritoneum, with low systemic toxicity. In histopathological examinations, greater hepatocellular necrosis and apoptosis, hepatic fibrosis around the central vein and degeneration with minor fatty change were observed with RSV than with NANO-RSV. Inflammation with proximal tubular necrosis and renal glomerulus swelling were also observed, together with slight elevation of several biochemical parameters in both the RSV and NANO-RSV groups. In order to increase the beneficial effects and reduce risks associated with resveratrol nanocrystals, additional factors such as dose, genetic factors, health status, and the nature of the target cells should also be considered.

Effects of aflatoxin B1 and monensin interaction on liver and intestine of poultry – influence of a biological additive (Pichia kudriavzevii RC001)

The aim of this study was to evaluate the effects of aflatoxin B1 (AFB1) and monensin (MONS) interaction on the liver and intestinal histological changes in poultry, and the influence ofPichia kudriavzevii RC001. One-day-old commercial line (Ross 308) broilers (n=120) were individually weighed and randomly assigned to 8 treatments (15 broilers/treatment, 5 broilers per cage and 3 replicates/treatment). The experimental diets were: Group 1: basal diet (BD); Group 2: BD + MONS (50 mg/kg); Group 3: BD +P. kudriavzevii RC001 (1 g/kg); Group 4: BD + AFB1 (100 μg/kg); Group 5: BD + MONS +P. kudriavzevii RC001; Group 6: BD + AFB1 +P. kudriavzevii RC001; Group 7: BD + AFB1 + MONS +P. kudriavzevii RC001; Group 8: BD + AFB1 + MONS. When MONS was added, the typical AFB1 macroscopic and microscopic alterations were intensified. TheP. kudriavzevii RC001 cytotoxicity and genotoxicity assays with Vero cells and with broiler chicken’s erythrocytes, demonstrated thatP. kudriavzevii RC001 neither were non-cytotoxic nor genotoxic. When MONS was added in the presence ofP. kudriavzevii RC001, the toxic effect of AFB1 on liver was not prevented. WhenP. kudriavzevii was present alone, the same prevention of the pathological damage was observed in the intestine of poultry fed with AFB1. The smallest apparent absorption area was obtained when AFB1 and MONS were added in the feed (P&lt;0.05). AFB1 and MONS interaction demonstrated important toxic effects. AlthoughP. kudriavzevii was effective in ameliorating the adverse effects of AFB1 alone on liver pathology and gut morphology, it was not able to diminish the toxic effects of AFB1 in presence of MONS. It suggests thatP. kudriavzevii could be used as feed additive or counteracting the toxic effects of AFB1 in poultry production in the absence of MONS.

Histological and immunological insights to hydatid disease in camels.

To investigate the immuno-histological evidences in viable and non-viable hydatid cysts obtained from naturally infected camels. A cohort study (February 2018-December 2019), a total of 15 hydatidosis-infected camels from slaughter houses in Cairo were involved. Specimens were investigated for parasite viability, liver histological changes, IL-17A cytokine immunohistochemical expressions in the adventitial layer, and the anti-nuclear antibodies (ANAs) immunofluorescent expression in the metacestode's structures. Real-Time Quantitative -Morphocytometry and SPSS were utilized. Multi-focal lesions and high viability were found in 60% of the cases. Overall accumulation of collagen associated the parasite establishment that involved infiltrations of mononuclear cells with significantly increased IL-17A expression. Interestingly, the ANAs appeared to have a role in the immune-defense against the metacestode showing different patterns. ANAs production correlated with IL-17A expression and the viability of the parasite. IL-17A responses in hydatidosis is associated with collagen deposition and ANA production as a sort of anti-parasite immunity in a viability dependent manner.

Non-Clinical Investigation of Tuberculosis Drugs: Conjugated Norbornene- Based Nanocarriers Toxic Impacts on Zebrafish

INTRODUCTION: Rifampicin conjugated (R-CP), and rifampicin -isoniazid dual conjugated (RI-CP) norbornene-derived nanocarriers are newly designed for pH stimuli-responsive delivery of tuberculosis (TB) drugs. Its biosafety level is yet to be well established. OBJECTIVES: To assess the impacts of the nanocarriers on liver cells using zebrafish animal model and human liver cell line model (HepG2). METHODS: Initially, lethal dose concentration for the norbornene-derived nanocarrier systems in zebrafish was determined. The toxic effects were analysed at the sub-lethal drug concentration by histopathological study, total GSH level, gene expression and DNA damage in zebrafish liver cells. Fish erythrocyte nuclear abnormalities were also evaluated. Cell viability and oxidative stress level (ROS generation) after exposure to the nanoconjugates was determined using HepG2 cell in the in vitro study. RESULTS: In vivo studies of both R-CP and RI-CP showed 100% mortality at 96 hours for exposure concentration &gt;100mg/l and showed toxic changes in zebrafish liver histology, GSH, and DNA damage levels. A noticeable upregulated PXR, CYP3A and cyp2p6 genes was observed in RI-CP exposure than in RIF or R-CP molecules. The in vitro study revealed a dose-dependent effect on cell viability and ROS generation for RIF, R-CP and RI-CP exposures in HepG2 cells. CONCLUSION: The current study reports that the rifampicin conjugated (R-CP) and rifampicin-isoniazid conjugated (RI-CP) norbornene derived nanocarriers exhibit enhanced toxic responses in both adult zebrafish and HepG2 cells. The pH-sensitive norbornene derived nanocarriers on conjugation with different drugs exhibited varied impacts on hepatic cells. Hence the present investigation recommends a complete metabolomics analysis and norbornene carrier-drug interaction study to be performed for each drug conjugated norbornene nanocarrier to ensure its biosafety.

Effects of Lead Nitrate Induced Histological Changes in Liver of Male Sprague Dawley Rats

Lead is a highly toxic agent and a potent risk factor for various diseases as its quantity in an environment is increasing day by day. Aim: To observe and analyze the lead nitrate induced histomorphological changes in the liver of Sprague Dawley rats. Study Design: Experimental Study. Methodology: Animals of group A (control) were fed on normal diet but the animals of group B were given 50mg/kg of lead nitrate dissolved in 10ml of distilled water through oral gavage for 14 days daily. SPSS version 22 was used for data analysis. All the quantitative data was expressed as means ± SD. One Way ANOVA followed by Post Hoc Tukey test was applied. Results: Degenerative effects were noted. The number of Inflammatory and Kupfffer cells is increased with decreased in the body weight. Steatosis and central vein congestion were also present. Conclusion: It was concluded that degenerative effects histologically may be due to oxidative stress produced by formation of free radicals and denaturation of proteins by lead nitrate. Keywords: Lead, Liver, Central Vein Congestion, Oxidative Stress and Free Radicals.

Long noncoding RNAs associated with nonalcoholic fatty liver disease in a high cholesterol diet adult zebrafish model

The mechanism of nonalcoholic fatty liver disease (NAFLD) has not been completely revealed. In this study, we investigated the association of liver histological changes and long noncoding RNAs (lncRNAs) in the NAFLD zebrafish model. Forty zebrafish were fed a high-cholesterol diet (1.5 g per day) for 8 weeks. We measured fatty liver changes in the zebrafish liver using oil red O staining and divided them into two groups based on high and low scores. We pooled each group of zebrafish livers and identified lncRNAs, miRNAs, and mRNAs using Next-generation sequencing. Human homologs of lncRNAs were identified using ZFLNC, Ensembl, and NONCODE. We found several significant genes, including 32 lncRNAs, 5 miRNA genes, and 8 protein-coding genes, that were associated with liver metabolism and NAFLD-related functions in zebrafish. In particular, eight conserved human homologs of lncRNAs were found. We discovered the human homologs of eight lncRNA candidates from fatty liver zebrafish for the first time. The spectrum of biological mechanisms by which lncRNAs mediate their functional roles in NAFLD in a high cholesterol diet adult zebrafish model remains to be uncovered.

Fasting augments pyrrolizidine alkaloid-induced hepatotoxicity.

Pyrrolizidine alkaloids (PAs) are phytotoxins widely present in various natural products and foodstuffs. The present study aims to investigate the effects of fasting on PA-induced hepatotoxicity and the underlying biochemical mechanisms. The results of hepatotoxic study showed that 15-h overnight fasting significantly exacerbated the hepatotoxicity of retrorsine (RTS, a representative toxic PA) in fasted rats compared to fed rats, as indicated by remarkably elevated plasma ALT and bilirubin levels and obvious liver histological changes. Further toxicokinetic studies revealed that fasting significantly enhanced cytochromes P450 enzymes (CYPs)-mediated metabolic activation of RTS leading to increased formation of pyrrole-protein adducts and thus decreased the in vivo exposure and excretion of both parent RTS and its N-oxide metabolite. Metabolic studies demonstrated that fasting induced enzyme activities of CYP1A2, CYP2B6 and CYP2E1 that participated in catalyzing RTS to its reactive pyrrolic metabolites. Moreover, fasting also dramatically decreased hepatic glutathione (GSH) content, which restricted the detoxification of GSH by neutralizing the reactive pyrrolic metabolite of RTS, further contributing to the enhanced hepatotoxicity. The present findings may have an impact on future PA toxicity tests with different dietary styles and/or risk assessment of metabolite-mediated toxins by considering the profound effects of fasting.

Protective effects of cerium oxide nanoparticles in non-alcoholic fatty liver disease (NAFLD) and carbon tetrachloride-induced liver damage in rats: Study on intestine and liver

Background and aimsNanoparticles could represent a therapeutic approach for the treatment of various diseases. It has been reported that cerium oxide nanoparticles (CeO2 NPs) have potential useful effects. Therefore, we aimed to examine the protective effects of the CeO2 NPs in two models of liver injury, non-alcoholic fatty liver disease (NAFLD) and carbon tetrachloride (CCl4)-induced liver fibrosis, in rats. MethodsIn this experimental study, male rats were randomly divided into different experimental groups including: Experiment 1; group1: healthy rats received normal saline, 2: CCl4 group, 3: CCl4 + nanoparticle. Experiment 2; group1: healthy rats received chow diet, 2: NAFLD group, 3: NAFLD + nanoparticle. The oxidative stress markers were determined in the liver and intestine. Tumor necrosis factor-α (TNF-α) levels were measured by ELISA. Histopathological changes of liver and intestine were evaluated by light microspore. ResultsTotal antioxidant capacity (TAC) and glutathione (GSH) levels significantly decreased, while malondialdehyde (MDA) and total oxidant status (TOS) were significantly increased in the liver, and intestine of the NAFLD and CCl4 group compared with control rats. However, the use of nanoparticles significantly normalized these markers. The levels of the TNF-α were significantly reduced in the nanoparticle group as compared with NAFLD model and CCl4-treated rats. CeO2 NPs also normalized the liver and intestinal histological changes. ConclusionsOur finding revealed that CeO2 NPs has potential protective effects by increasing antioxidant activity, and reducing inflammation.

Liujunzi Decoction ameliorated cisplatin-induced anorexia by inhibiting the JAK-STAT signaling pathway and coordinating anorexigenic and orexigenic neuropeptides in rats

Ethnopharmacological relevanceAs a traditional Chinese formula, Liujunzi Decoction (LJZD) originated from the Yi Xue Zheng Zhuan, and has a promising effect in treating chemotherapy-induced anorexia (CIA). Aim of the studyThe present study aims to investigate whether LJZD acts on interleukin-6 (IL-6)/leptin mediated janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling pathway that regulates hypothalamus anorexigenic and orexigenic peptides to ameliorate CIA, and also elucidates the potential mechanism by metabolomic analysis. Materials and methodsNetwork pharmacology analyses were conducted to screen out potential targets and pathways. The CIA rat model was established via an intraperitoneal injection of cisplatin. The histological changes of gastric antrum, liver and ileum were observed by HE staining. The serum levels of leptin, ghrelin, IL-6 and growth differentiation factor 15 (GDF15) were measured by ELISA. The JAK1/2 and STAT levels in gastric antrum and hypothalamus were detected by Western blot. The transcriptions of gastric antrum and hypothalamus IL-6R mRNA, and hypothalamus cocaine- and amphetamine-regulated transcript (CART), pro-opiomelanocortin (POMC), thyrotropin-releasing hormone (TRH), upregulated orexigenic peptides neuropeptide Y (NPY), and agouti-related protein (AGRP) mRNA were assessed by RT-qPCR. The blood samples of control, model and high dose LJZD groups were analyzed by metabolomic. ResultsNetwork pharmacology highlighted the IL-6/leptin mediated JAK-STAT signaling pathway, which regulated downstream anorexigenic and orexigenic peptides in hypothalamus. LJZD ameliorated CIA via stimulating food intake and water consumption in rats. Cisplatin-induced gastric antrum, liver, ileum injuries were ameliorated, serum leptin level reduction was elevated, and ghrelin, IL-6, GDF15 level increases were decreased after LJZD treatments. In gastric antrum and hypothalamus, LJZD inhibited cisplatin-induced activation of JAK-STAT signaling pathway, downregulated the transcriptions of downstream anorexigenic peptides CART, POMC, TRH, and upregulated orexigenic peptides NPY, AGRP in hypothalamus. Importantly, the effect of LJZD in treating CIA might partly relate to the improvements of 23 abnormal metabolites. ConclusionThis study implies that inhibiting JAK-STAT signaling pathway, regulating the expressions of anorexigenic and orexigenic peptides, and mediating various metabolic pathways might be potential mechanisms of LJZD's effect against CIA.

Besifovir therapy improves hepatic histology and reduces covalently closed circular DNA in chronic hepatitis B patients.

Besifovir dipivoxil maleate (BSV) was reported to have comparable antiviral efficacy and superior renal and bone safety to tenofovir disoproxil fumarate (TDF) in chronic hepatitis B (CHB) patients. The present study aims to evaluate changes of liver histology and intrahepatic covalently closed circular DNA (cccDNA) levels by BSV treatment in comparison with TDF therapy. This is a subset study of the phase 3 trial comparing BSV with TDF. Among them, only CHB patients willing to participate in a histologic evaluation study were enrolled. Liver histologic examination and intrahepatic cccDNA quantification were performed. A total of 46 CHB patients received liver biopsies (BSV, n=29; TDF, n=17). After 48weeks of treatment, virological response rate was comparable between the groups (P=0.707). Follow-up liver biopsies showed that necroinflammation was significantly improved in the both groups. However, the histological response rate defined as the proportion of subjects whose modified histologic activity index score decreased by ≥2 without deterioration in fibrosis was higher in the BSV group than in the TDF group (77.8% vs 36.4%, P=0.048). The proportion of subjects with Ishak fibrosis score 3 or more decreased from 77.7% to 55.5% in the BSV and that decreased from 72.7% to 45.4% in the TDF group. The intrahepatic cccDNA significantly decreased from baseline after 48weeks of BSV or TDF treatment (P<0.001) without intergroup differences (P=0.349). The BSV therapy improves hepatic histology and decreases intrahepatic cccDNA in CHB patients.

Favorable effects of Anethum graveolens on liver oxidative stress and cholesterol 7 alpha-hydroxylase levels in non-alcoholic fatty liver disease (NAFLD) rat models

BackgroundHigh-fat high-cholesterol diet induces a phenotype similar to non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) in humans. In NAFLD and NASH, cholesterol and bile acid metabolisms are impaired to accumulate lipids and toxic bile acids along with cholestatic hepatic damage. Recently, the use of herbal-derived cholesterol lowering products has attracted much attention as possible therapeutic strategies for NAFLD. Hence, the aim of this study was to determine the effects of an Anethum graveolens (dill) on liver cholesterol 7 alpha-hydroxylase and liver fat accumulation in rats. MethodThirty-six rats were randomly divided into 6 groups (n = 6) and received normal diet (ND) or a mixture of chow diet+2% cholesterol+0.5% cholic acid + 20% corn oil as high cholesterol/fat (HC–HF) diet (NAFLD model). Animals were also treated daily with dill tablet or dill extract (300 mg/kg). At the end of the 30 days experiments, serum and liver lipid profile and liver total antioxidant capacity were determined. Cholesterol 7 alpha-hydroxylase mRNA and protein expression levels were determined in the liver and histopathological changes in liver tissues were analyzed by microscope. ResultsLipid profiles significantly decreased in dill treated groups (p < 0.05). Liver total antioxidant capacity significantly (p < 0.05) increased and MDA levels markedly (p < 0.05) reduced both in dill tablet and dill extract treated groups (p < 0.05). Both types of treatments caused significant increases in liver cholesterol 7 alpha-hydroxylase gene expression (p < 0.05). Histopathological examinations showed that treatment with dill normalized the hypercholesterolemia-induced changes in liver histology. ConclusionAdministration of dill significantly reduced liver fat, oxidative stress and increased cholesterol 7 alpha-hydroxylase enzyme at the both mRNA and protein levels. Dill extract was found more effective than its commercially available tablet.

Pyrrolizidine Alkaloid-Induced Hepatotoxicity Associated with the Formation of Reactive Metabolite-Derived Pyrrole-Protein Adducts.

Pyrrolizidine alkaloids (PAs) with 1,2-unsaturated necine base are hepatotoxic phytotoxins. Acute PA intoxication is initiated by the formation of adducts between PA-derived reactive pyrrolic metabolites with cellular proteins. The present study aimed to investigate the correlation between the formation of hepatic pyrrole–protein adducts and occurrence of PA-induced liver injury (PA-ILI), and to further explore the use of such adducts for rapidly screening the hepatotoxic potency of natural products which contain PAs. Aqueous extracts of Crotalaria sessiliflora (containing one PA: monocrotaline) and Gynura japonica (containing two PAs: senecionine and seneciphylline) were orally administered to rats at different doses for 24 h to investigate PA-ILI. Serum alanine aminotransferase (ALT) activity, hepatic glutathione (GSH) level, and liver histological changes of the treated rats were evaluated to assess the severity of PA-ILI. The levels of pyrrole–protein adducts formed in the rats’ livers were determined by a well-established spectrophotometric method. The biological and histological results showed a dose-dependent hepatotoxicity with significantly different toxic severity among groups of rats treated with herbal extracts containing different PAs. Both serum ALT activity and the amount of hepatic pyrrole–protein adducts increased in a dose-dependent manner. Moreover, the elevation of ALT activity correlated well with the formation of hepatic pyrrole–protein adducts, regardless of the structures of different PAs. The findings revealed that the formation of hepatic pyrrole–protein adducts—which directly correlated with the elevation of serum ALT activity—was a common insult leading to PA-ILI, suggesting a potential for using pyrrole–protein adducts to screen hepatotoxicity and rank PA-containing natural products, which generally contain multiple PAs with different structures.

Zerumbone Exhibit Protective Effect against Zearalenone Induced Toxicity via Ameliorating Inflammation and Oxidative Stress Induced Apoptosis.

Zearalenone are widely occurring food contaminants that cause hepatotoxicity. This research work aimed to investigate how zerumbone, a plant-derived dietary compound, can fight ZEA-induced hepatotoxicity. ZER is found to increase the cells’ toxin resistance. This study was performed on mice challenged with ZEA. The administration of ZER decreased the level of alkaline phosphatase and alanine aminotransferase (ALT). Simultaneously, ZER attenuated the inflammatory response via significantly reducing the levels of pro-inflammatory factors, including interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) in serum. Pretreatment with ZER reduced the hepatic malondialdehyde (MDA) concentration, as well as the depletion of hepatic superoxide dismutase (SOD), hepatic glutathione (GSH), and hepatic catalase (CAT). Moreover, it significantly ameliorated ZEA-induced liver damage and histological hepatocyte changes. ZER also relieved ZEA-induced apoptosis by regulating the PI3K/AKT pathway and Nrf2 and HO-1 expression. Furthermore, ZER increasingly activated Bcl2 and suppressed apoptosis marker proteins. Our findings suggest that ZER exhibits the ability to prevent ZEA-induced liver injury and present the underlying molecular basis for potential applications of ZER to cure liver injuries.

QSHY Granules Promote White Adipose Tissue Browning and Correct BCAAs Metabolic Disorder in NAFLD Mice.

PurposeWhite adipose tissue (WAT) has positive effects on peripheral metabolism parameters and liver energy metabolism. This study aimed to explain the pharmacological mechanism of Qushi Huayu (QSHY) granules in the treatment of nonalcoholic fatty liver disease (NALFD) mice based on branched-chain amino acid (BCAA) catabolism and WAT browning.Patients and MethodsThirty C57BL/6J mice were randomly divided into a (Ctrl) control group, fed with a control diet, a NAFLD model group, fed with a high-fat and high-sugar (HFHS) diet, and a QSHY granules treatment (HFHS+QSHY) group, administered with QSHY granules. After 14 weeks of feeding, HFHS+QSHY group mice were administered QSHY granules through oral gavage for 6 weeks. The metabolic parameters were assessed, the circular and fecal BCAA content was observed, and liver and epididymal WAT (eWAT) were collected for pathological, quantitative real-time polymerase chain reaction, and Western blotting analyses.ResultsCompared with the HFHS group, mice in the HFHS+QSHY group demonstrated restored liver histological changes, ameliorated hepatocyte steatosis, and alleviated inflammatory cell infiltration. Consistent with the pathological changes, QSHY granules significantly reduced the elevated levels of liver triglycerides, and serum alanine aminotransferase, and it relieved hypercholesterolemia and insulin resistance in mice with HFHS-induced NAFLD. Furthermore, it corrected BCAA metabolic disorders in serum and feces and promoted the expression of BCAA catabolic genes in the eWAT of HFHS mice. QSHY granules also increased the expression of phosphorylated AMP-activated protein kinase (AMPK) protein, up-regulating the protein expression of the AMPK/SIRT1/UCP-1 pathway in the eWAT.ConclusionQSHY granules improved hepatic steatosis and corrected the BCAA disorder in NAFLD mice, and the related mechanisms regulated the AMPK/SIRT1/UCP-1 pathway and promoted WAT browning.

Effect of indomethacin (Non steroidal anti-infilammatory drug) on intestinal permeability and liver functions

Abstract Background Many theories tried to connect liver and gut as they have close anatomical, metabolic, and immunologic connections so exposure to large numbers of foreign molecules coming from the gastrointestinal tract via the portal vein like the bacterial components and other products may lead to liver damage by disturbing intestinal barrier and permeability which can be induced by indomethacin, one of non-steroidal anti inflammatory drugs(NSAIDs). Aim To investigate whether liver injury is linked to disturbance in intestinal permeability or not. Methodology Indomethacin was used to induce dysbiosis in male Wistar rats which were divided into two groups: Naive and Indomethacin groups. The later was received indomethacin (3mg\kg\day) by oral gavage. Liver function tests, micrbiological and histological studies were performed. Results Indomethacin induced elevation in liver enzymes, bacteremia and histological changes as compared to vehicle group. Conclusions Indomethacin induced dysbiosis with disturbance in the intestinal permeability that yield to hepatic injury.