Hepatoprotective Effect of β-Chitosan from Gladius of Sepioteuthis lessoniana Against Carbon Tetrachloride-Induced Oxidative Stress in Wistar Rats

Chitosan has attracted much attention as a biomedical material, owing to its unique biological activities. In this study, hepatoprotective effect of β-chitosan obtained from the gladius of squid Sepioteuthis lessoniana was studied against carbon tetrachloride (CCl₄)-induced oxidative stress and liver injury in rats. The rats that received β-chitosan along with the administration of CCl₄ showed significantly decreased plasma and tissue alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities and total cholesterol, triglyceride (TG) and free fatty acid (FFA) contents, whereas the treatment with β-chitosan alone markedly increased rat hepatic and circulatory superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) and reduced glutathione (GSH) levels and decreased the malondialdehyde level. Histopathological observations recommended the marked hepatoprotective effect of β-chitosan. The CCl₄-induced alterations on circulatory and hepatic antioxidant defence system were normalised by β-chitosan, and it could be concluded that the hepatoprotective effect of chitosan may be due to its antioxidant and antilipidemic property. Therefore, β-chitosan could be considered as antihepatotoxic agent.     

Comprehensive analysis of the compound profiles of Folium Camelliae Nitidissimae extract by ultrafast liquid chromatography with quadrupole–time-of-flight mass spectrometry and hepatoprotective effect against CCl4-induced liver injury in mice

Folium Camelliae Nitidissimae (jinhuacha in Chinese, JHC) is a kind of caffeine-less tea with antioxidant, antitumor and antibacterial effects. Studies on the chemical profiles and hepatoprotective effects of JHC extracts have not been systematically conducted so far. This study comprehensively investigated the compound profiles of JHC extract by ultrafast liquid chromatography with quadrupole time-of-flight tandem mass spectrometry. We also determined JHC's hepatoprotective effects against CCl₄-induced liver injury in mice. A JHC extract was administered orally to mice at 1.95 and 7.80 g/kg body weight once daily for 14 consecutive days prior to CCl₄ treatment. Eighty-four compounds including flavonoids, organic acids, catechins, coumarins, phenylpropanol, amino acids, anthraquinones, saponins and nucleosides in JHC extract were authentically identified or tentatively identified by comparing MS information and retention times with those of authentic standards or available references. JHC administration significantly decreased elevated levels of aspartate aminotransferase and alanine aminotransferase in mouse serum, inhibited hepatic malondialdehyde formation and enhanced glutathione and superoxide dismutase activities in the liver of CCl₄-treated mice. The histological observations also further supported the results. These results demonstrate that JHC contains various chemical compounds and its hepatoprotective effects against CCl₄-induced liver injury correlated with decreasing lipid oxidation are significant.     

Chemical constituents and protective effect of Ficus ingens (Miq.) Miq. on carbon tetrachloride-induced acute liver damage in male Wistar albino rats

The aim of the present study was to investigate the chemical constituents and hepatoprotective effect of Ficus ingens (Miq.) Miq. (Moraceae) extract against carbon tetrachloride-induced acute liver damage in male Wistar albino rats. The ethanol extract of F. ingens, was subjected to phytochemical study. In addition, its acute and sub-chronic toxicities were assessed. Eight compounds were isolated from this plant and identified as β-sitosterol, β-sitosterol glucoside, chryasophanol, 7-hydroxy-2,5 dimethyl chromen-4-one, quercetin, Aloe emodin glucoside, rutin and Patuletin-3′-O-methyl-3-O-rutinoside. The structure elucidation was based on ¹H and ¹³C NMR, proton–proton correlation spectroscopy (¹H–¹H Cosy), distortionless enhancement by polarization transfer (DEPT), Heteronuclear Multiple-Quantum Correlation (HMQC), and heteronuclear multiple bond correlations spectrum (HMBC). Hepatotoxicity induced with CCl₄ was evidenced by elevation of liver marker enzymes (ALT, AST, ALP and LDH) and TB content in serum. In addition, antioxidant enzymes were drastically inhibited with significant reduction of GSH and increased LPO in liver homogenate of CCl₄-intoxicated rats. Pre-treatment with F. ingens (200 and 400 mg/kg) and silymarin (50 mg/kg) avoided the changes observed in CCl₄-intoxicated rats. In conclusion, the ethanol extract of F. ingens showed protective activity against liver injury, which might be developed into a new hepatoprotective agent.     

Low‐level Laser Therapy Ameliorates CCl4‐induced Liver Cirrhosis in Rats

This study investigated the effects of low‐level laser therapy (LLLT) in the liver function, structure and inflammation in a experimental model of carbon tetrachloride (CCl₄)‐induced liver cirrhosis. Wistar rats were divided into Control, LLLT, CCl₄ and CCl₄+LLLT groups. CCl₄ groups received CCl₄ (0.4 g kg^?1; i.p.), three times a week, for 12 weeks. A 830 nm LLLT was performed with a continuous wave, 35 mW, 2.5 J cm^?2 per point, applied to four points of the liver (right and left upper and lower extremities, in the four lobes of the liver) for 2 weeks. Liver structure and inflammation (cirrhotic areas, collagen deposition, inflammation, density of Kupffer and hepatic stellate cells) and function (aspartate aminotransferase, alkaline phosphatase, gamma glutamyltransferase, lactate dehydrogenase, total proteins and globulins) were evaluated. LLLT significantly reduced CCl₄‐increased aspartate aminotransferase (P < 0.001), alkaline phosphatase (P < 0.001), gamma‐glutamyl transferase (P < 0.001) and lactate dehydrogenase (P < 0.01) activity, as well as total proteins (P < 0.05) and globulins (P < 0.01). LLLT also reduced the number of cirrhotic areas, the collagen accumulation and the hepatic inflammatory infiltrate. Of note, LLLT reduced CCl₄‐increased number of Kupffer cells (P < 0.05) and hepatic stellate cells (P < 0.05). We conclude that LLLT presents beneficial effects on liver function and structure in an experimental model of CCl₄‐induced cirrhosis.     

Angelica gigas NAKAI and Its Active Compound,Decursin, Inhibit Cellular Injury as an Antioxidant by the Regulation of AMP-Activated Protein Kinase and YAP Signaling

Natural products and medicinal herbs have been used to treat various human diseases by regulating cellular functions and metabolic pathways. Angelica gigas NAKAI (AG) helps regulate pathological processes in some medical fields, including gastroenterology, gynecology, and neuropsychiatry. Although some papers have reported its diverse indications, the effects of AG against arachidonic acid (AA)+ iron and carbon tetrachloride (CCl₄) have not been reported. In HepG2 cells, AA+ iron induced cellular apoptosis and mitochondrial damage, as assessed by mitochondrial membrane permeability (MMP) and the expression of apoptosis-related proteins. On the other hand, AG markedly inhibited these detrimental phenomena and reactive oxygen species (ROS) production induced by AA+ iron. AG activated the liver kinase B1 (LKB1)-dependent AMP-activated protein kinase (AMPK), which affected oxidative stress in the cells. Moreover, AG also regulated the expression of yes-associated protein (YAP) signaling as mediated by the AMPK pathways. In mice, an oral treatment of AG protected against liver toxicity induced by CCl₄, as indicated by the plasma and histochemical parameters. Among the compounds in AG, decursin had antioxidant activity and affected the AMPK pathway. In conclusion, AG has antioxidant effects in vivo and in vitro, indicating that natural products such as AG could be potential candidate for the nutraceuticals to treat various disorders by regulating mitochondrial dysfunction and cellular metabolic pathways.     

Protective Effect of Thymus serrulatus Essential Oil on Cadmium-Induced Nephrotoxicity in Rats,through Suppression of Oxidative Stress and Downregulation of NF-κB,iNOS, and Smad2 mRNA Expression

The purpose of the research was to examine the protective effect of essential oil from Thymus serrulatus Hochst. ex Benth. (TSA oil) against cadmium (Cd)-induced renal toxicity. The experimental protocol was designed using 30 healthy adult Wistar albino rats allocated into five groups containing six animals in each group. Group 1 was treated as normal control and groups 2, 3, 4, and 5 were treated with cadmium chloride (CdCl₂, 3 mg/kg, IP) for 7 days. Group 3 was also treated with silymarin (100 mg/kg, PO) as a standard group, while groups 4 and 5 were administered with TSA oil at doses of 100 and 200 mg/kg PO, respectively. The nephrotoxicity was measured with various parameters such as kidney function markers, oxidative stress markers (glutathione (GSH) and malondialdehyde (MDA)), and messenger ribonucleic acid (mRNA) expression levels of inflammatory factors. The histological studies were also evaluated in the experimental protocol. The CdCl₂-treated groups showed a significant increase in the levels of serum kidney function markers along with MDA levels in kidney homogenate. However, renal GSH level was found to be reduced significantly. It was found that CdCl₂ significantly upregulated the nuclear factor levels of kappaB (NF-κB p65), inducible nitric oxide synthase (iNOS), and small mothers against decapentaplegic (Smad2) as compared to the normal control group. On the other hand, TSA oil significantly improved the increased levels of serum kidney function markers, non-enzymatic antioxidants, and lipid peroxidation. In addition, TSA oil significantly downregulated the increased expression of NF-κB p65, iNOS, and Smad2 in Cd-intoxicated rats. Moreover, the histological changes in the tissue samples of the kidney of Cd-treated groups were significantly ameliorated in the silymarin- and TSA-oil-treated groups. The present study reveals that TSA oil ameliorates Cd-induced renal injury, and it is also proposed that the observed nephroprotective effect could be due to the antioxidant potential of TSA oil and healing due to its anti-inflammatory action.     

Schizocalyx cuspidatus (A. St.-Hil.) Kainul. & B. Bremer extract improves antioxidant defenses and accelerates the regression of hepatic fibrosis after exposure to carbon tetrachloride in rats

The aim of this study was to investigate the effect of leaves extract of Schizocalyx cuspidatus (A. St.-Hil.) Kainul. & B. Bremer on hepatic morphofunctional dysfunction induced by carbon tetrachloride (CCl₄). Liver lesions were induced via intraperitoneal administration of CCl₄ every 48 h for 12 days. Forty-nine rats were randomised into seven groups: G1: CCl₄; G2: CCl₄ (animals euthanised 24 h after last CCl₄ application); G3: CCl₄ + DMSO; G4: SCE 400 mg/kg; G5: DMSO (700 μl); G6: CCl₄ + SCE 200 mg/kg and G7: CCl₄ + SCE 400 mg/kg. SCE administration resulted in reduction in hydroperoxide levels, lipidic droplets and necrosis compared to G1, G2 and G3. There was an increase in the amount of collagen fibres in G1, G2 and G3 compared to the groups. These results show that the extract of SCE leaves has great potential for the recovery of liver damage after the application of CCl₄.     

Enhancement of bioavailability and hepatoprotection by silibinin through conversion to nanoparticles prepared by liquid antisolvent method

The current research was intended to establish the impact of Silibinin nanoparticles (SB-APSP) produced by the antisolvent precipitation with a syringe pump (APSP). The in-vivo bioavailability and hepatoprotective activity of SB-APSP were evaluated in experimental animals. To determine the pharmacokinetic parameters, silibinin and its nanoparticles were given orally to rabbits at a dose of 50 mg/Kg body weight. Blood samples were drawn at different time intervals and were analyzed using HPLC. The bioavailability of un processed silibinin was lower as compared to silibinin nanoparticles (3.45 ± 0.07 and 23.76 ± 0.07 µg/mL respectively). The AUC and C_max of SB-APSP were found to be 15.56 and 6.88 folds greater for nanoparticles when compared to silibinin. Hepatoprotective study in Male Sprague Dawley rats revealed that SB-APSP provide better recovery of the damaged liver cell induced by CCl₄. Histopathology of the liver revealed that SB-APSP provide better protection to the liver cells from the damage induced by CCl₄ and maintained the hepatic lobule histopathology more efficiently. It was concluded that the SB-APSP can more effectively protect the liver in experimental animals in a far better way compared to the un-processed Silibinin and could be used as an efficient hepatoprotective agent.     

Evaluation of antioxidant and immunity-enhancing activities of Sargassum pallidum aqueous extract in gastric cancer rats

The effect of Sargassum pallidum (brown seaweed) aqueous extract on the immunity function and antioxidant activities in was studied gastric cancer rats. Treatment with Sargassum pallidum aqueous extract at oral doses 400, 600 or 800 mg/kg body weight was found to provide a dose-dependent protection against N-methyl-N′-nitro-Nnitrosoguanidine (MNNG)-induced immunity damage and oxidative injury by enhancing serum interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-10 (IL-10) levels, decreasing interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α) levels, preserving normal antioxidant enzymes activities, and by inhibiting lipid peroxidation in gastric mucosa. It can be concluded that Sargassum pallidum aqueous extract may enhance the immunity and antioxidant activities in gastric cancer rats.     

Elevated levels of liver methylglyoxal and d‐lactate in early‐stage hepatitis in rats

Methylglyoxal (MGO) is highly cytotoxic and its levels are elevated in diabetes, nephropathy and atherosclerosis. However, it has never been studied in liver disease. For this reason, we aimed to assess the levels of MGO and its metabolite d ‐lactate in an early hepatitis model. Wistar rats were administered CCl₄ (0.75 mL/kg, i.p.) to induce hepatitis. In either CCl₄‐treated or untreated rats, alanine transaminase and aspartate transaminase levels did not change over the course of the study, indicating that significant liver damage did not occur following CCl₄ treatment. However, the levels of MGO and d ‐lactate were higher in the livers of CCl₄‐treated animals than in untreated animals (MGO: 128.2 ± 18.8 and 248.1 ± 64.9 μg/g protein, p < 0.01; d ‐lactate: 0.860 ± 0.040 and 1.293 ± 0.078 μmol/g protein, respectively p < 0.01). Furthermore, in untreated and treated animals, serum d ‐lactate levels were 57.65 ± 2.59 and 92.16 ± 16.69 μm and urine d ‐lactate levels were 1.060 ± 0.007 and 1.555 ± 0.366 μmol/mg UCr, respectively (p < 0.01). These data show that in this model of early‐stage liver damage, the levels of MGO and its metabolite d ‐lactate are elevated and that d ‐lactate could be useful as a reference marker for the early stage of hepatitis.     

Saxifraganoids A and B,two novel cucurbitane triterpenoid glycosides from Saxifraga umbellulata var. pectinata

Two novel cucurbitane triterpenoid glycosides, named saxifraganoids A (1) and B (2), were isolated from Saxifraga umbellulata var. pectinata. Their structures including absolute configurations were elucidated based on the analysis of spectroscopic data (1D, 2D NMR and HRMS), and single-crystal X-ray diffraction. Compound 1 represents the first example of cucurbitane triterpenoid with a Δ¹⁷⁽²⁰⁾, and compound 2 contained an unusual N-acetylglucosamine at C-16. The protective effects against liver injury induced by carbon tetrachloride (CCl₄) in the human embryonic-liver L-02 cells of these two compounds were evaluated.     

Synthesis of trimethylhydroquinone derivatives as anti-allergic agents with anti-oxidative actions

A novel series of trimethylhydroquinone derivatives was synthesized and evaluated for their anti-lipid peroxidation activity in rat liver microsomes, inhibition of rat basophilic leukemia-1 (RBL-1) cell 5-lipoxygenase and 48 h homologous passive cutaneous anaphylaxis (PCA) activity in rats. 4-[4-[4-(Diphenylmethyl)-1-piperazinyl]-butoxy]-2,3,6-trimethyl phenol (9c) exhibited the ability to inhibit Fe(3+)-ADP induced NADPH dependent lipid peroxidation (IC50 = 5.3 x 10(-7) M), 5-lipoxygenase ((IC50 = 3.5 x 10(-7) M) and PCA reaction (57% inhibition at 100 mg/kg p.o.).     

Potential cardioprotective influence of bupropion against CCl4-triggered cirrhotic cardiomyopathy

Bupropion, an atypical anti-depressant and smoking cessation aid, attenuates complications arising from the activation of inflammatory and oxidative pathways. In this study, the effect of bupropion on an inflammatory and oxidative condition induced by carbon tetrachloride (CCl₄) namely cirrhotic cardiomyopathy (CCM) was investigated in rats. CCM was induced by intraperitoneal injection of CCl₄ (0.4 g/kg, i.p.). Bupropion was treated orally at doses 30 and 60 (mg/kg, p.o.) for 8 weeks. CCl₄ treatment significantly lowered hepatic antioxidant enzymes catalase (CAT), superoxide dismutase (SOD), and glutathione (GSH) while enhanced Malondialdehyde (MDA). Elevations in serum nitric oxide (NO) metabolites nitrite/nitrate, and cardiac tumor necrosis factor alpha (TNF-α) and interleukin 1-beta (IL-1β) levels were observed. Cirrhosis also decreased contractility in response to isoproterenol (10^?10 to 10^?5 M). The spleen weight and intrasplenic pressure increased and QTc, QRS and RR intervals prolonged. Pathological damages in the liver for example focal necrosis, fibrosis and the hepatic blocking increased. On the other hand, bupropion increased GSH, CAT and SOD and lowered MDA. Bupropion reduced NO metabolites and TNF-α levels and decreased IL-1β. The cardiac contractile force improved at maximal effect (Rmax) 10^-5 M by bupropion. The intrasplenic pressure was reduced by bupropion. Bupropion reduces QTc, QRS and RR intervals and the liver tissue damages. Bupropion played a cardioprotective role reducing inflammatory and oxidative factors. It may recover the impairment of cardiac contractility and hyperdynamic condition in CCM, and this effect could be mediated at least in part by a NO-dependent mechanism.     

Green biosynthesis of Pt-nanoparticles from Anbara fruits: Toxic and protective effects on CCl4 induced hepatotoxicity in Wister rats

Platinum Nanoparticles (PtNPs) are synthesized from the Anbara fruit (Phoenix dactylifera L.) and are characterized using various spectroscopic analytical methods. These PtNPs were used to study the Hepatotoxic and Hepatoprotective effects on acute liver damage caused by CCl₄ in Wister rats. Seventy-two rats of both sexes are divided into twelve groups and are treated with PtNPs and aqueous Anbara extract (AAE). Histopathological examinations were performed to identify the toxic effects on the vital organs of the rats. Hepatoprotective activity was monitored by observing the serobiochemical and hematological parameters and the intensity of hepatic marker enzymes alanine transferase (ALT), aspartate amino transferase (AST) and alkaline phosphatase (ALP) in the organs such as liver, intestine and kidney. Considerable experimental results were obtained when compared with the standard drug Silymarine. The PtNPs and AAE were proven to have protective activity of enzymes in the liver of Wister rats.     

Synthesis and antioxidative/anti-inflammatory activity of novel fullerene–polyamine conjugates

(E)-4-(Fullerenopyrrolidin-1-yl)-3-methylbut-2-enoic acid and its corresponding succinimidyl ester, readily obtained through Prato-type modification of C₆₀, were used for the selective N-acylation of polyamines. The thus obtained conjugates were evaluated for their antioxidative and anti-inflammatory activity and their cytotoxicity was determined. Members of this family of compounds showed interesting anti-lipid peroxidation, anti-lipoxygenase and anti-inflammatory activity and comparable cytocompatibility to spermidine.     

Hibiscus sabdariffa synthesized gold nanoparticles ameliorate aluminum chloride induced memory deficits through inhibition of COX-2/BACE-1 mRNA expression in rats

Alzheimer’s disease (AD) is a major health challenge worldwide, especially among the elderly. The disease is associated with cognitive and memory deficits. This study investigated the effect of Hibiscus sabdariffa synthesized-gold nanoparticles (HS-AuNPs) on AlCl₃-induced memory deficits in rats. Forty-two male Wistar rats were divided into six groups (n = 7). Group I served as control. Rats in group II - V were exposed to AlCl₃ (100 mg/kg) to induce AD. Group III - V rats were treated with 5 mg/kg donepezil, 5 and 10 mg/kg HS-AuNPs, respectively, for 14 days. Behavioral tests were carried out on the rats on day 28 and 42. At the end of animal experiment, rats were sacrificed and used for various biochemical assays and gene expression. The AD rats showed memory and learning impairment, and these conditions were ameliorated by HS-AuNPs. Significant (p < 0.05) elevation in the activities of acetylcholinesterase, monoamine oxidase and adenosine deaminase, as well as malondialdehyde levels was noted. A significant reduction in the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and reduced glutathione (GSH) noted in AlCl₃-induced rats were ameliorated by the 5 and 10 mg/kg b.w. doses of HS-AuNPs. In addition, the increased mRNA expression of cyclooxygenase-2 (COX-2) and beta-secretase 1 (BACE-1) caused by AlCl₃ were assuaged by the HS-AuNPs treatment. Based on the activities of HS-AuNPs against AlCl₃-induced AD, HS-AuNPs could be considered a potential therapeutic agent for managing AD.     

Comparative study on Artemisia halodendron Turcz. and its two related plants by GC-MS analysis and protective effect against carbon tetrachloride-induced hepatotoxicity in mice

A rapid method had been used for comparative study on Artemisia halodendron Turcz. and its two related plants by gas phase-mass spectrometry (GC-MS). The comparison of the volatile oils obtained in three plants by GC-MS were similar in 20 compositions. However, n-Hexadecanoic acid (10.40%), Biphenyl (7.867%) and 9,12-Octadecadienoic acid (7.25%) were the predominant in the volatile oils of A. halodendron Turcz., whereas these constituents did not exist in the other two plants. And the study investigated the effect of three plants against CCl₄-induced hepatotoxicity in mice. 70% ethanol extracts of A. halodendron Turcz. showed weaker protective effect than the other two plants. It suggested that they provide a basis for the identification of the A. halodendron Turcz. from the other two plants and the ethanol extract from three plants exerted a protecting effect against hepatotoxicity.     

Protective effects of vitamin E against CCl<Subscript>4</Subscript>-induced hepatotoxicity in rabbits

The influence of CCl₄ on the activity of superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR), the value of the total antioxidant status (TAS), and the concentration of malonic dialdehyde (MDA) and glutathione (GSH) was monitored in plasma or whole blood of rabbits. The administration of CCl₄ caused the increase of the SOD activity to approximately 150 % and the decrease in the activity of GPx and GR by about 50 %. These changes were accompanied with the increase in TAS value and MDA concentration and the decrease of GSH concentration. The effect of CCl₄ was suppressed by the previous 7 days lasting or simultaneous administration of vitamin E. Oxidative stress caused by CCl₄ was accompanied by the development of reactive oxygen forms, especially superoxide radical anion.     

Anti-oxidative action of ent-kaurene diterpenoids

Nine ent-kaurene diterpenoids, leukamenin E, glaucocalyxin A, wangzaozi A, epinodisinol, epinodosin, rabdosin B, rabdosinate, lasiokaurin and oridonin, were separated from Isodon racemosa (Hemsl) Hara and Isodon japonica (Burm.f) Hara var. galaucocalyx (maxin). The protection against DNA damage induced by hydrogen peroxide in human peripheral blood mononuclear cells (PBMCs) and inhibition of lipid peroxidation in rat liver microsome were studied with comet assay and thiobarbituric acid reactive substances determination. All nine diterpenoids showed concentration-dependent protection in DNA damage in human PBMCs induced by 50 μM H₂O₂. The effects were similar and weaker than quercetin. The inhibitions of lipid peroxidation were obviously difference. Rabdosin B and oridonin were the strongest inhibitors, followed by lasiokaurin and wangzaozin A. Rabdosinate was the weakest and others were medium. The structure-activity relationship is discussed.