Changes In Liver Tissue Research Articles

Pseudo-targeted metabolomics study of immune stress-mediated idiosyncratic liver injury induced by synergistic effects of bavachin and epimedin B

Chinese patent medicine preparations containing Epimedii Folium and Psoraleae Fructus have been associated with the occurrence of idiosyncratic drug-induced liver injury(IDILI). However, the specific toxic biomarkers and mechanisms underlying these effects remain unclear. This study aimed to comprehensively assess the impact of bavachin and epimedin B, two principal consti-tuents found in Psoraleae Fructus and Epimedii Folium, on an IDILI model induced by tumor necrosis factor-α(TNF-α) treatment, both in vitro and in vivo. To evaluate the extent of liver injury, various parameters were assessed. Lactate dehydrogenase(LDH) release in the cell culture supernatant, as well as the levels of alanine aminotransferase(ALT) and aspartate transaminase(AST) in mouse plasma were measured. Additionally, histological analysis employing hematoxylin-eosin staining was performed to observe liver tissue changes indicative of the severity of liver injury. Furthermore, a pseudo-targeted metabolomics approach was employed, followed by multivariate analysis, to identify differential metabolites. These identified metabolites were subsequently subjected to Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis. The results showed that at the cellular level, after 2 hours of TNF-α stimulation, bavachin significantly increased the release of LDH in HepG2 cells compared to the normal group and the group treated alone; after the combination of bavachin and epimedin B, the release of LDH further significantly increased on the original basis. Similarly, although the individual or combination treatments of bavachin and epimedin B did not induce liver injury in normal mice, the combination of both drugs induced marked liver injury in TNF-α treated mice, leading to a significant elevation in plasma AST and ALT levels and substantial infiltration of inflammatory immune cells in the liver tissue. Pseudo-targeted metabolomics analysis identified seven common differential metabolites. Among these, D-glucosamine-6-phosphate, N1-methyl-2-pyridone-5-carboxamide, 17beta-nitro-5a-androstane, irisolidone-7-O-glucuronide, and N-(1-deoxy-1-fructosyl) valine emerged as potential biomarkers, with an area under the curve(AUC) exceeding 0.9. Furthermore, our results suggest that the metabolism of nicotinic acid and nicotinamide, as well as the linoleic acid metabolic pathway, may play pivotal roles in bavachin and epimedin B-induced IDILI. In conclusion, within an immune-stressed environment mediated by TNF-α, bavachin and epimedin B appear to induce IDILI through disruptions in metabolic processes.

Protective role of virgin coconut oil on potent biochemical biomarkers in Wistar rat model of comorbid depression.

Chronic stress arises from stressful situations in day-to-day life that are ignored or managed incorrectly. Long-term stress can have negative effects, especially when it plays a role in the development of neurological illnesses. Severe stress can also negatively impact emotional well-being. Virgin coconut oil (VCO) has numerous health advantages. The aim of this study was to assess how VCO affected the biochemical and behavioral characteristics of Wistar albino rats exposed to chronic, unpredictable stress. Healthy Wistar albino rats (150-200 gm) were split into two groups: experimental group and control group. Based on stress exposure and treatment with VCO and antidepressants, they were further divided into various subgroups. A chronic, unpredictable stress procedure was given for 21 days. After the experimental procedure, the rats were anesthetized, and through a cardiac puncture, blood was collected. The liver and brain were dissected to estimate different biochemical markers. VCO proved to be a protective agent against chronic, unpredictable stress-induced changes in the biochemical parameters, hepatic enzyme activity, lipid profile, oxidative stress, and cognition. VCO might be helpful as an effective natural treatment that can be utilized to effectively combat chronic, unpredictable stress-induced changes in brain and liver tissue.

The Effect of Single Clove Garlic Extract (Allium sativum) Against Aspartame-Induced Hepatotoxicity in Diabetic Rats

Background: Aspartame is a widely used synthetic sweetener used for dietary control and by diabetics. Objectives: This study aims to investigate the effect of a single garlic clove extract against aspartame-induced hepatotoxicity in diabetic rats. Methods: Forty-eight experimental male albino rats were randomly divided into eight groups (6 rats per group) as follows: Group (G)1: served as normal control and received distilled water orally, G2: rats treated with single clove garlic (SCG) extract (0.5 g/kg body weight), G3: rats were treated with SCG extract (0.5 g/kg body weight) and alkaline phosphatase (ALP) (200 mg/kg body weight), G4: rats treated with ASP (200 mg/kg body weight), G5: was the diabetic control group (induced by alloxan (ALX) 120 mg/kg body weight), G6: diabetic rats were treated with SCG extract (0.5 g/kg body weight), G7: diabetic rats were treated with SCG extract (0.5 g/kg body weight) and ASP (200 mg/kg body weight) and G8: diabetic rats were treated with ASP 200 mg/kg body weight. Results: The results obtained showed that treatment with ASP caused a significant increase in serum levels of serum alanine transaminase (ALT), aspartate transaminase (AST), and ASP in SCG extract-treated rats in G3 and G4 and diabetic rats in G7 and G8, while treatment with SCG extract caused a significant decrease in serum levels of ALT, AST and ALP in SCG treated rats in G2 and G6 and diabetic rats in G7 compared to the control group (G1). After treatment with ASP, histologic changes in the liver were observed in G4, which were more pronounced in G8, indicating liver damage compared to the control group, while treatment with SCG extract showed further changes in liver tissue in the diabetic rats of G7 and G8. Conclusion: The present study suggests that administering ASP in normal rats leads to liver dysfunction. Moreover, our results proved that the application of ASP in diabetic rats may cause additional damage compared to ASP in normal rats. This study demonstrated that treatment with SCG extract significantly attenuated the biochemical and histopathologic changes induced by ASP and alloxan. From the data obtained, it appears that treatment with SCG extract has a protective effect against the toxicity of ASF and alloxan on the liver of normal and diabetic rats.

Therapeutic potentials of N-acetylcysteine immobilized polyrhodanine nanoparticles toward acetaminophen-induced acute hepatotoxicity in rat.

N-acetylcysteine (NAC) is a recommended drug for treating acetaminophen (APAP) intoxication. Due to NAC's low bioavailability, this study aimed to use polyrhodanine (PR) nanoparticles (NPs) as a drug carrier to improve the effectiveness of NAC. After preparation and characterization of NAC loaded on PR, 30 rats were randomly divided into five groups of six. The first group (control) received normal saline. Groups 2-5 were treated with normal saline, PR, NAC, and NAC loaded on PR, respectively. The treatments were started 4 h after oral administration of APAP (2000 mg kg-1 ). After 48 h, the animals were anesthetized, and liver function indices and oxidative stress were measured in tissue and serum samples. The APAP administration can increase aminotransferases and alkaline phosphatase enzymes in serum, decreasing the total antioxidant capacity and thiol groups and increasing lipid peroxidation in liver tissue. Administration of PR-NAC could effectively improve the level of serum-hepatic enzymes, total antioxidant capacity and thiol groups, lipid peroxidation, and pathological changes in liver tissue in animals poisoned with APAP. PR-NAC has a significant therapeutic effect on preventing acute hepatotoxicity caused by APAP, and its effectiveness can be associated with an improvement in the oxidant/antioxidant balance of liver tissue.

Phytochemical constituents of bark essential oils of Cinnamomum zeylanicum Blume and effects on liver tissue of rats

Cinnamomum zeylanicum Blume is an evergreen tropical tree belonging to the Lauraceae family; it is a useful plant in traditional and modern medicines. Essential oils of Cinnamomum zeylanicum were prepared and identified using gas chromatography–mass spectrometry (GC-MS). For histological study 80 adult male rats were employed in this study. It is the same weight (30 ±5 gm) and 75 days in age. The animals were divided into 4 groups, with ten rats in each group. The results indicated that C. zeylanicum bark contained 27 different phytochemical components. The main components included Cinnamaldehyde (2-Propenal, 3-phenyl-) (46.46%), 9-Methoxybicyclo, [6.1.0] nona-2,4,6-triene (31.31%), alpha-, Muurolene (7.14%) and Copaene (1.63%). Sections of livers were examined for histological abnormalities, such as the breakdown of the liver architecture and increased inflammation, in comparison to control samples, some hepatocytes were swollen with pyknotic, large nuclei and dilated sinusoids. As well as in the rats treated with noticed sever congestion of central vein (CV), degeneration and sluggish of endothelial lining larger, Bile ducts hyperplasia and necrotic hepatocytes. It can be deduced that the main component of cinnamon bark oil is cinnamaldehyde and the liver displayed some tissue changes, including hepatocyte necrosis and the existence of steatosis foci. Histological and cellular changes in liver tissue were dramatically attenuated by C. zeylanicum essential oil.

A study of the anti-fibrotic effect of ghrelin on mice with nonalcoholic steatohepatitis

Objective: To study the anti-fibrotic effect of ghrelin on high-fat diet-induced non-alcoholic steatohepatitis (NASH) in mice. Methods: 24 male C57BL/6 mice were randomly divided into a normal diet group, a normal diet + ghrelin group, a high-fat diet group, and the high-fat diet + ghrelin group. The HFD and HFD+ghrelin groups were fed high-fat diet for 16 weeks to induce non-alcoholic steatohepatitis. Among them, the NCD+ghrelin group and HFD+ghrelin group were continuously given ghrelin intervention (11nmol·kg(-1)·d(-1)) for 2 weeks after feeding for 14 weeks. 16 mice were euthanized on weekends. The plasma levels of alanine aminotransferase (ALT) and hyaluronic acid (HA) were measured in mice. The content of hydroxyproline (Hyp) was determined in liver tissue. RT-qPCR was used to detect the mRNA expression levels of transforming growth factor β1 (TGF-β1) and collagen types I, III, and IV in liver tissue. A Western blot was used to detect the expression level of the α-smooth muscle actin (α-SMA) protein in liver tissue. HE staining was used to observe the morphological changes in liver tissue. VG staining was used to observe the fibrotic condition in liver tissue. Results: Compared with the NCD group, plasma ALT (266.80±146.80)U/L, HA (219.00±39.47) ng/ml levels, Hyp content (0.35±0.05)μg/mg prot (P < 0.05), mRNA expression levels of transforming growth factor β1 (TGF-β1) and collagen types I, III, IV (P < 0.05), and the expression level of α-SMA protein in the HFD group were significantly increased (P < 0.05), with congestion in the hepatic central lobular veins, hepatocytes swelling, and deposition of a large amount of collagen fibers in liver tissue. Compared with the HFD group, plasma ALT (57.17±20.88)U/L, HA (75.68±8.40)μg/mg levels, Hyp content (0.19±0.07)μg/mg prot, mRNA expression levels of transforming growth factor β1 (TGF-β1) and collagen types I, III, IV (P < 0.05), and the expression level of α-SMA protein in the HFD+ghrelin mice group was significantly reduced (P < 0.05), with only mild sinusoidal congestion in the liver tissue but significant improvement and reduction in liver injury and collagen fiber deposition. Conclusion: Ghrelin has a significant improvement effect on liver fibrosis in NASH mice.

Physiological and histopathological effects of polystyrene nanoparticles on the filter-feeding fish Hypophthalmichthys molitrix

Excessive use of plastics in daily life is causing plastic pollution in aquatic environment and threatening the aquatic life. Therefore, research on the plastic pollution in aquatic environment is crucial to understand its impact and develop effective solution for safeguarding aquatic life and ecosystem. The current study investigated the effects of water borne polystyrene nanoparticles (PS-NPs) on hemato-immunological indices, serum metabolic enzymes, gills, and liver antioxidant parameters, plasma cortisol level and histopathological changes in liver and gill tissues of the widely distributed fish Hypophthalmichthys molitrix. The fingerlings of H. molitrix were exposed to different concentrations (T1–0.5, T2–1.0, and T3–2.0 mg/L) of PS-NPs respectively for 15 days consecutively. Our results indicated the dose dependent negative effects of PS-NPs on the physiology and histopathology of H. molitrix. Immuno-hematological indices showed significant increase in WBCs count, phagocytic activity, and lysozyme activity, while decreased RBC count, Hct%, Hb level, total proteins, IgM, and respiratory burst activity were observed. The levels of antioxidant enzymes like SOD, CAT and POD showed the decreasing trends while metabolic enzymes (AST, ALT, ALP and LDH), LPO, ROS activities and relative expressions of SOD1, CAT, HIF1-α and HSP-70 genes increased with increased concentrations of PS-NPs. Moreover, blood glucose and cortisol levels also showed significant increasing trends with dose dependent manner. Histopathological examination indicated moderate to severe changes in the gills and liver tissues of the group treated with 2.0 mg/L of PS-NPs. Overall, the results showed the deleterious effects of PS-NPs on physiology, immunity, metabolism, and gene expressions of H. molitrix. It is concluded that particulate plastic pollution has deleterious effects on filter feeding fish, which might affect human health through food chain and particulate chemical toxicity.

Constitutive androstane receptor agonist initiates metabolic activity required for hepatocite proliferation

Constitutive androstane receptor (CAR, NR1I3) activation by chemical compounds evokes liver hyperplasia in rodent. 1,4-Bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP), a mouse CAR agonist, is most commonly used to study chemically induced liver hyperplasia and hepatocyte proliferation in vivo. TCPOBOP is potent murine liver chemical mitogen, which induces rapid direct liver hyperplasia independent of liver injury. In recent years, a lot of data has been accumulated on the transcription program that characterizes TCPOBOP-induced hepatocyte proliferation. However, there are scarce data about metabolic requirements of hepatocytes dividing upon treatment with xenobiotics. In present study, we employed liquid chromatography - mass spectrometry technology combined with statistical analysis to develop a metabolite profile of small biomolecules, to identify key metabolic changes in male mouse liver tissue after TCPOBOP administration. Analysis of biochemical pathways of the differentially affected metabolites in mouse livers demonstrated significant TCPOBOP-mediated enrichment of several processes including those relevant to nucleotide metabolism, amino acid metabolism, and energy substrate metabolism. Our findings provide evidence to support the conclusion that CAR agonist, TCPOBOP, initiates an intracellular program that promotes the global coordinated metabolic activities required for hepatocyte proliferation. Our metabolic data may provide novel insight into the biological mechanisms that occur during TCPOBOP-induced hepatocyte proliferation in mice.

Chronic toxicity and liver histopathology of mosquito fish (Gambusia holbrooki) exposed to natural and modified nanoclays

Nanoclays are found in the air, water, and soil, and modified nanoclays are being developed and used in several consumer products. For example, modified nanoclays are used to remove pollutants from wastewater. Ironically, however, nanoclays are now considered emerging contaminants. Indeed, release of modified nanoclays in aquatic systems, even as remediating agents, could adversely affect associated wildlife. However, aquatic organisms have interacted with natural nanoclays for millennia, and it is unclear if modified nanoclays induce stronger effects than the nanoclays that occur naturally. The concentrations over which nanoclays occur and illicit negative effects are not well studied. This study investigated the dose response of a natural nanoclay (Na+montmorillonite) relative to two modified nanoclays (Cloisite®30B and Novaclay™) on survival, body condition, and liver pathomorphology of Gambusia holbrooki after 14 days of exposure. Although none of the nanoclays affected survival and body condition of G. holbrooki over 14 days, each nanoclay induced histopathological changes in liver tissues at very low concentrations (LOAEL: 0.01 mgL−1). The effects of nanoclays on hepatic cell circulatory (blood cell aggregation with increased number of Kupffer cells and hemosiderin deposits), regressive (hepatocyte vacuolization), and degenerative (cell death) changes of mosquito fish varied among nanoclay types. Novaclay™ at low concentrations caused circulatory changes on hepatic tissues of G. holbrooki, whereas both natural nanoclays and Cloisite®30B showed little effect on circulatory endpoints. In contrast, all of the nanoclays induced regressive and degenerative changes on liver tissues of mosquito fish across all concentrations tested. This study clearly reveals that natural and modified nanoclays have important health implications for fish and other aquatic organisms. Consequently, the widespread use of modified nanoclays in several applications and increased release of natural nanoclays through erosion or other processes needs to be evaluated in more detail especially in the context of their safety for aquatic systems.

Morphological changes in liver tissues of rats under the exposure of ecotoxicants and perinatal prophylaxis

BACKGROUND: The high sensitivity of the liver to chemicals is due to its leading role in their metabolism. During the biotransformation of ecotoxicants, highly reactive intermediate products may be formed and free radical oxidation may be initiated, which may result in liver damage.&#x0D; MATERIALS AND METHODS: The experiment was carried out on outbred white rats weighing 180250 g. A total of 50 animals were involved in the experiment. All animals were divided into 5 groups: control and 4 experimental ones. All rats in the experimental groups were subjected to inhalation exposure to gasoline and formaldehyde vapors. In the 1st (control) group only poisoning with ecotoxicants was used, in the 2nd group peptinsorbent (apple pectin) was used against the background of poisoning with ecotoxicants, in the 3rd group a membrane protector lemongrass, in the 4th group a beets, in the 5th experimental group peptinsorbent, membrane protector and beets. We examined pieces of liver and rats that were subjected to histological processing. Using a LEICA RM 2145 rotary microtome (Leica Microsystems, Germany), histological sections with a thickness of 58 m were prepared. Stained sections were examined and photographed using an Axio Imager Z1 light microscope (Carl Zeiss, Germany).&#x0D; RESULTS: The liver structure of rat pups born from female rats exposed to subchronic gasoline and formaldehyde poisoning throughout pregnancy has pronounced pathomorphological signs characteristic of hepatosis, turning into toxic hepatitis. The use of lemongrass, peptinsorbent and beets separately, along with intoxication of pregnant rats, somewhat reduced the degree of pathomorphological changes in the liver of born rat pups, but not dramatically. When using a combined mixture (apple pectin + membrane protector lemongrass + beets), the liver structure of the rat pups subsequently born was preserved relatively better than in the control group, with the exception of certain areas of the liver in which hemostasis and moderately pronounced dystrophic changes in hepatocytes were detected.&#x0D; CONCLUSIONS: The combined mixture (apple pectin + membrane protector lemongrass + beets) has a more pronounced hepatoprotective effect compared to the separate use of each of its constituent substances and is effective as a hepatoprotective agent for liver damage from ecotoxicants.

A Novel Quinazoline Derivative Prevents and Treats Arsenic-Induced Liver Injury by Regulating the Expression of RecQ Family Helicase.

Arsenic is a carcinogenic metalloid toxicant widely found in the natural environment. Acute or prolonged exposure to arsenic causes a series of damages to the organs, mainly the liver, such as hepatomegaly, liver fibrosis, cirrhosis, and even hepatocellular carcinoma. Therefore, it is imperative to seek drugs to prevent arsenic-induced liver injury. Quinazolines are a class of nitrogen heterocyclic compounds with biological and pharmacological effects in vivo and in vitro. This study was designed to investigate the ameliorating effects of quinazoline derivatives on arsenic-induced liver injury and its molecular mechanism. We investigated the mechanism of the quinazoline derivative KZL-047 in preventing and ameliorating arsenic-induced liver injury in vitro by cell cycle and apoptosis. We performed real-time fluorescence quantitative polymerase chain reaction (qPCR) and Western blotting combined with molecular docking. In vivo, the experiments were performed to investigate the mechanism of KZL-047 in preventing and ameliorating arsenic-induced liver injury using arsenic-infected mice. Physiological and biochemical indices of liver function in mouse serum were measured, histopathological changes in liver tissue were observed, and immunohistochemical staining was used to detect changes in the expression of RecQ-family helicases in mouse liver tissue. The results of in vitro experiments showed that sodium arsenite (SA) inhibited the proliferation of L-02 cells, induced apoptosis, blocked the cell cycle at the G1 phase, and decreased the expression of RecQ family helicase; after KZL-047 treatment in arsenic-induced L-02 cells, the expression of RecQ family helicase was upregulated, and the apoptosis rate was slowed, leading to the restoration of the cell viability level. KZL-047 inhibited arsenic-induced oxidative stress, alleviated oxidative damage and lipid peroxidation in vivo, and ameliorated arsenic toxicity-induced liver injury. KZL-047 restored the expression of RecQ family helicase proteins, which is consistent with the results of in vitro studies. In summary, KZL-047 can be considered a potential candidate for the treatment of arsenic-induced liver injury.

Pathological and structural study of cardiac striated muscle and quadriceps along with the study of microscopic changes in liver, kidney and lung tissue following short-term and long-term resistance exercises in male rats

Background. Resistance exercise is a method designed to increase muscle strength and endurance, leading to beneficial physiological changes in various tissues. The aim of this study is to investigate the pathological and structural effects of short-term and long-term resistance training on various tissues of male rats, including cardiac striatum, quadriceps, liver, kidney, and lung tissue. Methods. Forty male Wistar rats were randomly divided into four groups: one-month control, four-month control, one-month exercise, and four-month exercise. After the exercise period, the animals were anesthetized and dissected to separate various tissues, which were then treated with formalin and prepared for analysis. Results. The study findings showed that liver tissue did not show significant histopathological changes in response to exercise. However, in the heart tissue, mild hyperemia and hypertrophy of muscle cells were observed in the exercise groups compared to the control groups. In the quadriceps muscle, hypertrophy was observed to a lesser extent in the one-month exercise group and to a greater extent in the four-month exercise group. There was a significant difference in the diameter of the muscle cells of the quadriceps muscle between the one-month and four-month exercise groups, indicating the beneficial effects of long-term exercise. Additionally, an increase in the size of the epithelial tissue of the urinary tubes was observed in both exercise groups, which indicates an increase in kidney function due to exercise. Conclusion. Overall, the results of this study show that resistance exercise can lead to beneficial physiological changes in various tissues, especially with long-term exercise. Understanding these changes can increase our knowledge about the benefits of exercise. Practical Implications. Resistance exercises, through actions such as hyperemia, hypertrophy of muscle cells, and hypertrophy of the epithelial tissue of urinary tubes, improve the efficiency of the heart, kidneys and muscles during sports exercises, especially with long-term exercise.

Changes of insulin receptors in high fat and high glucose diet mice with insulin resistance

ABSTRACT This study aimed to observe the expression of insulin-signaling molecules in different organs of mice with insulin resistance (IR). Firstly, mice were fed a high-fat and high-sugar diet (HF group) to establish an IR model, and the controls (NF group) were fed with a normal diet. Next, the weight, fasting blood glucose (FBG), serum insulin and insulin tolerance were detected. Pathological changes of liver tissues were observed by H&E staining. The expressions of INSR, IRS-1 and IRS-2 in the liver, skeletal muscle and ovary were measured by qRT-PCR and western blotting. As a result, compared with the NF group, the HF group mice had increased weight, FBG, insulin and IR index after 6-week of feeding as well as a worse performance in the insulin tolerance test and H&E staining showed fatty liver-like changes after 12-week of feeding, exhibited lower expression of INSR, IRS-1 and IRS-2 in the liver of mice at 6 and 12 weeks. The expression of INSR and IRS-1 in skeletal muscle tissues exhibited the same trend, while those in ovary organs showed the opposite trend. These results suggested that the insulin signaling alters in the liver, skeletal muscle and ovary organs with the progress of IR.

Gender differences in the development of experimental liver steatosis in laboratory rats

The aim. To study functional-morphological and biometric changes in the liver and lipid spectrum in an experiment in male and female laboratory rats when modeling fructose-induced liver steatosis. Materials and methods. The experimental study was conducted on 44 non-inbred sexually mature white rats, of which 20 were males aged 8-9 months with a body weight of 400-530 g. and 24 females aged 9-10 months with a body weight of 320-480 g. Modeling of liver steatosis was carried out for 28 days by adding fructose to drinking water throughout the experiment using 15%-th solution of fructose instead of drinking water. At the end of the experiment, body weight was measured, liver sampling for morphometric and histological studies and blood sampling for laboratory studies (transaminase, glucose and lipid spectrum levels) were performed. Results. When comparing body weight before the experiment and after its completion, a statistically significant increase in this indicator was found in females with experimental steatosis (p = 0.031), which indicates the formation of general obesity in them. The mass coefficient of the liver in the experimental groups of males and females with steatosis was significantly higher than in the controls (p= 0.009 and p = 0.009, respectively). During histological examination of liver tissue, the number of hepatocytes with steatosis in males and females in experimental models was significantly higher than in control groups and corresponded to the II-III degree of steatosis. A comparative analysis of the lipidogram parameters revealed that dyslipidemia developed during the formation of liver steatosis in animals of both groups with fructose-induced liver steatosis. Conclusion. In experimental modeling of fructose-induced liver steatosis in animals, regardless of gender, morphological changes in liver tissue are manifested by fatty dystrophy and hepatomegaly, dyslipidemia is registered. At the same time, males develop fermentemia, hyperglycemia without the formation of general obesity. In females, the course of experimental steatosis is accompanied by an increase in body weight without functional changes in the liver.

Beneficial effects of silibinin on serum lipids, bile acids, and gut microbiota in methionine-choline-deficient diet-induced mice.

Silibinin (SIL) is a flavonoid lignin isolated from the fruit and seeds of silybum marianum that exhibits good therapeutic potential for NASH. However, the effects of SIL on serum lipids, bile acids (BAs), and gut microbiota (GM) in NASH mice remain unknown. The present work aimed to explore the beneficial effects of SIL supplementation on serum lipids, bile acids, and gut microbiota in MCD mice. After male C57BL/6 mice were fed with a methionine-choline deficient (MCD) diet and simultaneously gavaged with SIL (20 mg/kg. d) for 8 weeks, the pathological changes of liver tissue were observed by oil red O, haematoxylin-eosin, and Masson tricolor staining; the levels of serum AST and ALT, and liver TG and MDA were detected by assay kits; metabonomics and 16S rDNA sequencing were used to analyze the composition of serum lipids and BAs and the abundance of GM; and the mRNA expression levels of hepatic genes related to BAs homeostasis were detected by RT-qPCR. The results indicated that SIL treatment decreased the levels of 26 lipids (including four arachidonic acids, seven FFAs, 12 acyl carnitines, and three GPs) and two BAs (23-DCA, GLCA), while Dubosiella increased the levels of 10 lipids (including TxB3, PG16:0_18:1, Cer t18:0/24:0 and 7 TGs), five BAs (β-MCA, α-MCA, UDCA, 3-oxo-DCA and HCA), and two GMs (Verrucomicrobiota and Akkermansiaceae) of MCD mice, but had no significant effect on the mRNA expression of CYP7A1, CYP27A1, Bsep, Mrp2, Ntcp, or Oatp1b2. Therefore, influencing GM composition and then regulating the levels of serum lipids and BAs through enterohepatic axis should be an important mechanism of SIL-induced alleviative effect on MCD mice. More importantly, we found that SIL had a good coordination in regulating the abundance of GM and the contents of serum lipids and BAs in MCD mice, that is, when the abundance of probiotics was up-regulated, the content of beneficial unsaturated fatty acids in serum was up-regulated, while the serum levels of harmful lipids and BAs were down-regulated. The alleviating effect of SIL on NASH may be closely related to the correction of intestinal bacteria disorder, serum bile acid, and lipid metabolic disturbance in mice.

The protective effect and mechanism of mangiferin on D‐galactose‐induced oxidative stress and cognitive impairment in aging mice by an integrated network pharmacology and experimental validation strategy

AbstractMangiferin (MAN) was a natural bioactive xanthone with remarkable antioxidative, anti‐inflammatory, and antiapoptotic effects. The purpose of this study to determine the protective influence of MAN on D‐galactose (D‐gal)‐induced aging and cognitive impairment, together with its underlying molecular mechanism. The network pharmacology molecular docking analysis revealed that MAN has a potential binding with aging‐related oxidative stress and apoptosis proteins. In D‐gal‐induced aging mice, MAN could significantly reduce D‐gal‐induced histopathological changes of liver and brain tissues. Moreover, MAN administration obviously increased activities of antioxidant enzymes (SOD, T‐AOC, GSH‐Px, and CAT) and decreased levels of AChE and MDA in the serum, liver, or brain tissues. Additionally, MAN alleviated learning and memory disorders and improved the exploration ability. Western blotting and immunohistochemical analysis results revealed that MAN could regulate the expressions of PI3K/Akt/Nrf2 signaling pathway‐related proteins and apoptotic‐related proteins (Bax, Bcl‐2, and Caspase‐9) in the liver tissues. Therefore, these findings suggested that MAN can be used as a potent dietary supplement in functional foods for the protection against aging‐related impairments.

Vitamin A accelerates the process of liver regeneration in the initial stages of Сu - induced fibrosis

Aim: To test the hypothesis about the possible role of vitamin A in normalizing the functional activity of the liver with Cu-induced fibrosis by increasing the regeneration process.&#x0D; Materials and methods: Experiments were conducted on 20 sexually mature male Wistar rats, which were divided into 4 groups: a control group that was not exposed to copper sulfate and vitamin A, a group that was at the initial stage of liver fibrosis, which was provided by three consecutive administrations of copper sulfate at a dose of 1 mg/100 g of weight (one series of injections), a group that was at the stage of intensive development of fibrosis (F2), which was carried out by two consecutive series of copper sulfate injections with an interval of 3 days between injections, and a group that received vitamin A three times daily in a dose of 300 IU/100 g of weight between two series of intoxication. Body weight dynamics, relative liver weight, histological changes in liver tissues and the number of binuclear hepatocytes were determined.&#x0D; Results: It has been found that animals with Cu-induced liver fibrosis did not gain or lose body weight, and the introduction of vitamin A ensured the restoration of body weight growth, and they slightly lagged behind the control group. In animals with liver fibrosis that received vitamin A, the relative weight of the liver was slightly increased and there were 2 times more binuclear hepatocytes. The structural organization of the liver tissue changed to a minor extent, and to the greatest extent there was an increase in the thickness of the Glisson’s capsule, in which immunocompetent cells were incorporated.&#x0D; Conclusions: Vitamin A contributed to the normalization of liver function against the background of the development of fibrosis. The mechanism of normalization can be ensured due to an increase in the number of binuclear hepatocytes, a slight increase in the relative weight of the liver, and was accompanied by an increase in the thickness of the Glisson’s capsule, in which immunocompetent cells were incorporated

Mining host candidate regulators of schistosomiasis-induced liver fibrosis in response to artesunate therapy through transcriptomics approach.

Artesunate (ART) has been reported to have an antifibrotic effect in various organs. The underlying mechanism has not been systematically elucidated. We aimed to clarify the effect of ART on liver fibrosis induced by Schistosoma japonicum (S. japonicum) in an experimentally infected rodent model and the potential underlying mechanisms. The effect of ART on hepatic stellate cells (HSCs) was assessed using CCK-8 and Annexin V-FITC/PI staining assays. The experimental model of liver fibrosis was established in the Mongolian gerbil model infected with S. japonicum cercariae and then treated with 20 mg/kg or 40 mg/kg ART. The hydroxyproline (Hyp) content, malondialdehyde (MDA) content, superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities in liver tissue were measured and histopathological changes of liver tissues were observed. Whole-transcriptome RNA sequencing (RNA-seq) of the liver tissues was performed. Differentially expressed genes (DEGs) were identified using bioinformatic analysis and verified by quantitative PCR (qPCR) and western blot assay. ART significantly inhibited the proliferation and induce the apoptosis of HSCs in a dose-dependent manner. In vivo, Hyp content decreased significantly in the ART-H group compared to the model (MOD) group and GPX activity was significantly higher in the ART-H group than in the MOD group. Besides, ART treatment significantly reduced collagen production (p <0.05). A total of 158 DEGs and 44 differentially expressed miRNAs related to ART-induced anti-schistosomiasis liver fibrosis were identified. The qPCR and western blot results of selected DEGs were consistent with the sequencing results. These DEGs were implicated in key pathways such as immune and inflammatory response, integrin-mediated signaling and toll-like receptor signaling pathways. ART is effective against liver fibrosis using Mongolian gerbil model induced by S. japonicum infection. We identified host candidate regulators of schistosomiasis-induced liver fibrosis in response to ART through transcriptomics approach.

Matrine disrupts Nrf2/GPX4 antioxidant system and promotes hepatocyte ferroptosis

Matrine (MT) is an alkaloid isolated from Sophora flavescens with various bioactivities and is widely used clinically. However, the broader its clinical use, the greater its toxicity concerns. We investigate the role of ferroptosis in MT-induced liver injury caused by an imbalance in the antioxidant pathway. Our results showed that MT could cause pathological changes in liver tissues and lead to a significant reduction in L02 cell viability. MT also reduced superoxide dismutase (SOD) and glutathione (GSH), increased malondialdehyde (MDA), reactive oxygen species (ROS), and lipid peroxidation levels, and disrupted iron homeostasis, leading to ferroptosis. In addition, MT decreased the protein levels of FTH, Nrf2, xCT, GPX4, HO-1 and ferroptosis suppressor protein 1 (FSP1) and increased the protein levels of TRF1 and DMT1, characteristic indicators of ferroptosis. Interestingly, the cytotoxic effects of MT were alleviated by ferroptosis inhibitor, Nrf2 agonist, or selenium supplementation. These results revealed that MT triggers hepatocyte ferroptosis by inhibiting the Nrf2/GPX4 antioxidant system.

Euphorbia factor L1 suppresses breast cancer liver metastasis via DDR1-mediated immune infiltration.

Euphorbia factor L1 (EFL1), a lathyrane-type diterpenoid from the medicinal herb Euphorbia lathyris L., has been documented to possess various pharmacologic actives. However, the function of EFL1 on breast cancer is not clear. In this study, we explored the effect and mechanism of EFL1 on breast cancer liver metastasis. Female BALB/c mice were subjected to breast cancer-surgical hepatic implantation (SHI) to establish breast cancer liver metastasis model in vivo. At 10 days post-surgery, mice were administrated with EFL1 once daily for a total of 2 weeks. Serum AST and ALT activities, abdominal circumference, peritoneal fluid, tumor weight and volume were determined to assess liver and mesenteric re-metastasis of breast cancer. H&E staining was used to observe morphology changes in tumor, liver and small intestine tissues. ELISA was applied to observe inflammatory levels. Tumor DDR1 expression and immune infiltration were determined using western blotting, immunohistochemistry and flow cytometer methods. Our results showed that EFL1 administration improved liver function (AST and ALT activities), ascites, liver metastasis and mesenteric re-metastasis in SHI mice. Also, SHI-induced inflammatory cell infiltration and IL-1β, IL-6, TNF-α generation in ascites were decreased by EFL1 treatment. Mechanism study revealed that EFL1 intervention enhanced the ratios of CD4+ and CD8+ and CD49b+(NK) T lymphocytes and decreased Treg cells through downregulating DDR1 in the tumor of SHI mice. Furthermore, overexpression of DDR1 abolished the anti-liver metastasis effect and pro-immune infiltration action of EFL1 in SHI mice. Together, our findings suggested that EFL1 protects against breast cancer liver metastasis in vivo by targeting DDR1-mediated immune infiltration.