Thioacetamide-induced Liver Fibrosis In Rats Research Articles

Therapeutic Effect of Hydrodynamics-Based Delivery of Matrix Metalloproteinase-13 Gene on Thioacetamide-Induced Liver Fibrosis in Rats

Liver cirrhosis is the final stage of chronic liver disease and can be life-threatening. Despite extensive studies on its treatment, a standard therapy is yet to be developed. Considering the complex mechanism of fibrogenic and fibrolytic processes in liver cirrhosis, combined therapy may have clinically significant effects on cirrhotic livers. In this study, we used thioacetamide (TAA) administration and matrix metalloproteinase-13 (MMP13) gene delivery to induce extracellular matrix generation and degradation in rats. The aim of this study was to determine whether hydrodynamics-based gene delivery of MMP13 to cirrhotic liver has regressive and suppressive effects on fibrogenesis. MMP13-encoding plasmids were hydrodynamically delivered to TAA-induced cirrhotic livers, and intravascular pressure was monitored. Therapeutic effect with and without continuous TAA exposure was assessed 8 weeks after the gene delivery. Test results indicated successful gene delivery and gene expression in the cirrhotic livers. Furthermore, microscopic imaging showed that MMP13 delivery resulted in significant degradation of fibrotic areas. Quantitative analysis of hydroxyproline content supported the microscopic findings. These results suggest that transgene delivery of MMP13 can be a promising candidate to treat liver fibrosis and that hydrodynamics-based gene delivery can be a good option for delivery of MMP13 to cirrhotic livers.

Hydroxysafflor yellow A protects against thioacetamide-induced liver fibrosis in rats via suppressing proinflammatory/fibrogenic mediators and promoting hepatic stellate cell senescence and apoptosis

Objective: To evaluate the effect of hydroxysafflor yellow A (HSYA) on thioacetamide-induced liver fibrosis. Methods: Thioacetamide was administered to rats intraperitoneally in doses of 200 mg/kg twice a week for 12 weeks. Thioacetamide-intoxicated rats were given silymarin (50 mg/kg) or HSYA (5 mg/kg) orally every day for 8 weeks. Liver enzymes, fibrosis markers, histological changes as well as immunohistochemistry of TNF-α, IL-6, p21, α-SMA, and caspase-3 were examined. The effect of HSYA on HSC-T6 activation/proliferation and apoptosis was also determined in vitro. Results: HSYA decreased liver enzymes, TNF-α, IL-6, and p21 expressions, hepatic PDGF-B, TIMP-1, TGF-β1, and hydroxyproline levels, as well as fibrosis score (S2 vs. S4) compared to the thioacetamide group. HSYA also downregulated α-SMA while increasing caspase-3 expression. Surprisingly, at 500 μg/mL, HSYA had only a slightly suppressive effect on HSC proliferation, with a 9.5% reduction. However, it significantly reduced TGF-β1, inhibited α-SMA expression, induced caspase-3 expression, and promoted cell senescence. Conclusions: HSYA may be a potential therapeutic agent for delaying and reversing the progression of liver fibrosis. More research on HSYA at higher doses and for a longer period is warranted.

A standardized pomegranate fruit extract ameliorates thioacetamide-induced liver fibrosis in rats via AGE-RAGE-ROS signaling

This work aimed to investigate a possible mechanism that may mediate the hepatoprotective effects of pomegranate fruit extract (PFE) against thioacetamide (THIO)-induced liver fibrosis in rats. Male Sprague Dawley rats were randomly allocated into four groups (n = 8 each): control; PFE (150 mg/kg/day, orally); THIO (200 mg/kg, i.p, 3 times a week); and THIO and PFE-treated groups. Oral PFE treatment decreased liver/body weight ratio by 12.4%, diminished serum function levels of ALT, AST, ALP, LDH, and total bilirubin, increased serum albumin, boosted hepatic GSH (by 35.6%) and SOD (by 17.5%), and significantly reduced hepatic levels of ROS, MDA, 4-HNE, AGEs, and RAGE in THIO-fibrotic rats relative to untreated THIO group. Moreover, PFE administration downregulated the hepatic levels of profibrotic TGF-β1 (by 23.0%, P < 0.001) and TIMP-1 (by 41.5%, P < 0.001), attenuated α-SMA protein expression, decreased serum HA levels (by 41.3%), and reduced the hepatic levels of the fibrosis markers hydroxyproline (by 26.0%, P < 0.001), collagen type IV (by 44.3%, P < 0.001) and laminin (by 43.4%, P < 0.001) compared to the untreated THIO group. The histopathological examination has corroborated these findings, where PFE decreased hepatic nodule incidence, attenuated portal necroinflammation and reduced extent of fibrosis. These findings may suggest that oral PFE administration could slow the progression of hepatic fibrogenesis via reducing hepatic levels of AGEs, RAGE, ROS, TGF-β1, and TIMP-1.

Dehydrozingerone ameliorates thioacetamide-induced liver fibrosis via inhibition of hepatic stellate cells activation through modulation of the MAPK pathway

Hepatic fibrosis is a progressive consequence of injury to the liver cells. Liver fibrosis causes hepatic dysfunction and also plays a key role in the pathogenesis of other chronic ailments. Dehydrozingerone (DHZ) is a half-structural analogue of curcumin and is known to have several therapeutic benefits. However, the impact of DHZ on liver fibrosis was not investigated. The current investigation attempted to determine the anti-fibrotic effect of DHZ against thioacetamide-induced liver fibrosis in rats and TGF-β-induced differentiation in human HSC-LX2 cells and to uncover the possible mechanisms. In in-vivo, DHZ significantly reduced the TAA-induced liver index and ameliorated the liver functional parameters. TAA elevated the fibrotic marker's expression in TAA control, on the other hand, DHZ treatment significantly mitigated the same in mRNA and protein levels. Additionally, these findings were supported by histological investigations and immunohistochemistry studies of the fibrotic marker's expressions. DHZ treatment effectively reduced oxidative stress by increasing catalase activity and decreased the expression of inflammatory markers (myeloperoxidase and neutrophil-elastase) in liver tissues. Additionally, collagen staining and histological findings confirmed that DHZ administration significantly reduced TAA induced pathological deformities and elevated collagen levels. In-vitro results showed that TGF-β-induced differentiation was suppressed by DHZ treatment in a dose-dependent manner. Mechanistic approaches in HSC-LX2 and liver tissues revealed that DHZ treatment mitigated fibrosis by modulating the MAPK-pathway. Overall, these results show that DHZ exhibited anti-fibrotic action by reducing fibrotic markers and their activities through regulation of the MAPK-pathway, suggesting that DHZ may be a promising therapeutic molecule for liver fibrosis.

Phytochemical profiling and anti-fibrotic activities of Plumbago indica L. and Plumbago auriculata Lam. in thioacetamide-induced liver fibrosis in rats

This study aimed at investigating the chemical composition and the hepatoprotective activities of Plumbago indica L. and P. auriculata Lam. LC–MS/MS analyses for the hydroalcoholic extracts of the aerial parts of the two Plumbago species allowed the tentative identification of thirty and twenty-five compounds from P. indica and P. auriculata, respectively. The biochemical and histopathological alterations associated with thioacetamide (TAA)-induced liver fibrosis in rats were evaluated in vivo where rats received the two extracts at three different dose levels (100, 200 and 400 mg/kg p.o, daily) for 15 consecutive days with induction of hepatotoxicity by TAA (200 mg/kg/day, i.p.) at 14th and 15th days. Results of the present study showed a significant restoration in liver function biomarkers viz. alanine transaminase (ALT), aspartate transaminase (AST), gamma glutamyl transferase and total bilirubin. The liver homogenates exhibited increased levels of antioxidant biomarkers: reduced glutathione (GSH) and catalase (CAT), accompanied with decline in malondialdehyde (MDA). Furthermore, treated groups exhibited a significant suppression in liver inflammatory cytokines: tumor necrosis factor-α (TNF-α) and interlukin-6 (IL-6), and fibrotic biomarker: alpha smooth muscle relaxant. Histopathological examination of the liver showed normality of hepatocytes. Noteworthy, P. indica extract showed better hepatoprotective activity than P. auriculata, particularly at 200 mg/kg. To sum up, all these results indicated the hepatoprotective properties of both extracts, as well as their antifibrotic effect was evidenced by reduction in hepatic collagen deposition. However, additional experiments are required to isolate their individual secondary metabolites, assess the toxicity of the extracts and explore the involved mechanism of action.

Protective effects of the carotenoids-rich alga Dunaliella salina against thioacetamide-induced liver fibrosis in rats

Protective effects of the carotenoids-rich alga Dunaliella salina against thioacetamide-induced liver fibrosis in rats

The involvement of TGF-β1 /FAK/α-SMA pathway in the antifibrotic impact of rice bran oil on thioacetamide-induced liver fibrosis in rats.

The objective of the current study is to investigate the effect of rice bran oil (RBO) on hepatic fibrosis as a characteristic response to persistent liver injuries. Rats were randomly allocated into five groups: the negative control group, thioacetamide (TAA) group (thioacetamide 100 mg/kg thrice weekly for two successive weeks, ip), RBO 0.2 and 0.4 groups (RBO 0.2mL and 0.4 mL/rat/day, po) and standard group (silymarin 100 mg/kg/day, po) for two weeks after TAA injection. Blood and liver tissue samples were collected for biochemical, molecular, and histological analyses. Liver functions, oxidative stress, inflammation, liver fibrosis markers were assessed. The obtained results showed that RBO reduced TAA-induced liver fibrosis and suppressed the extracellular matrix formation. Compared to the positive control group, RBO dramatically reduced total bilirubin, AST, and ALT blood levels. Furthermore, RBO reduced MDA and increased GSH contents in the liver. Simultaneously RBO downregulated the NF-κβ signaling pathway, which in turn inhibited the expression of some inflammatory mediators, including Cox-2, IL-1β, and TNF-α. RBO attenuated liver fibrosis by suppressing the biological effects of TGF-β1, α-SMA, collagen I, hydroxyproline, CTGF, and focal adhesion kinase (FAK). RBO reduced liver fibrosis by inhibiting hepatic stellate cell activation and modulating the interplay among the TGF-β1 and FAK signal transduction. The greater dosage of 0.4 mL/kg has a more substantial impact. Hence, this investigation presents RBO as a promising antifibrotic agent in the TAA model through inhibition of TGF-β1 /FAK/α-SMA.

Ameliorative effect of moringa and rosemary ethanolic extracts on thioacetamide-induced liver fibrosis in rats

Background/aim: Nutraceuticals have been extensively studied in recent years to find safe therapeutics of natural origin instead of relying only on pharmaceuticals. This study aimed to detect the hepato-protective role of moringa and rosemary ethanolic extracts on liver fibrosis induced by thioacetamide (TAA). Methods: This study was conducted on 60 male albino rats divided into four groups; control, TAA-group (received 100 mg/kg thioacetamide intraperitoneal twice /week for 18 weeks), moringa-protected group (received 300 mg/kg moringa ethanolic extract orally daily with TAA), rosemary-protected group (received 200 mg/kg rosemary ethanolic extract orally daily with TAA for 18 weeks). Results: There were significant increases in liver alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), malondialdehyde (MDA), and nitric oxide (NO) with significant decreases in reduced glutathione (GSH), superoxide dismutase (SOD) in the TAA-treated group with a high degree of fibrosis which extended to cirrhosis after 18 weeks. Meanwhile, both TAA-moringa and TAA-rosemary treated groups showed improvement in biochemical markers and fibrosis induced by TAA. Conclusion: This study proved that both moringa and rosemary could protect the liver against TAA-induced liver fibrosis and rosemary has greater protection than moringa.

Biochemical and Histopathological Effects of Colchicine and Moringa oleifera on Thioacetamide-Induced Liver Fibrosis in Rats

Liver fibrosis is the progressive accumulation of connective tissue in the liver, which can be caused by chronic liver injury of various etiologies. Moringa oleifera is a pan-tropical species is used in nurturing both animal and human as an excellent nutritive supplement. Colchicine is a plant that effective against gouty arthritis and other forms of rheumatic diseases (rheumatoid arthritis, familial Mediterranean fever, Bechet´s disease, etc. This study thrown light on the hepatoprotecitve effects of Moringa oleifera ethanolic leaves extract and colchicine on thioacetamide-induced liver fibrosis in rats. Liver function tests (serum ALT, AST, ALP, and Total protein) in addition to histopathological examination of the liver were performed. This study was carried out on a total number of 42 male albino rats were collocated into seven groups (6 rats per group). The experiment lasted for two months, through which all groups except for control and control positive were given Moringa oleifera ethanolic leaves extract and colchicine. Liver fibrosis was induced by intraperitoneal injection of thioacetamide (150 mg/kg) in groups II, V, VI &VII while other groups were injected with 0.9% normal saline of the same volume. Bodyweight was measured three times a week to detect the dose for each rat. The administration of thioacetamide leading a significant increase in serum liver enzyme level ALT, AST, ALP, and Total protein as compared to the control group, while treatment with colchicine and Moringa oleifera ethanolic leaves extract causing significant decreased serum liver enzyme level by (P<0.05) than the induced hepatic group. In general, there is no fundamental difference between groups V, VI, VII. Also revealed that the injection of thioacetamide (150 mg/kg) induced liver fibrosis characterized by a drastic decrease in total protein as compared to the control group by (P <0.05). The colchicine or Moringa oleifera ethanolic leaves extract was able to restore dysfunction. In general, the treatment with colchicine and Moringa oleifera showed good restore in biochemical function and histopathological of the liver. Also, we detected that there are no differences between them.

Hepatoprotective effect of Saccharomyces Cervisciae Cell Wall Extract against thioacetamide-induced liver fibrosis in rats

Fibrosis represents a common outcome of almost all chronic liver diseases and leads to an impairment of liver function that requires medical intervention. The current study aimed to evaluate the potential anti-fibrotic effect of Saccharomyces cervisciae cell wall extract (SCCWE) against thioacetamide (TAA)-induced liver fibrosis in rats (200mg/kg b.w. i.p. twice weekly for 6 weeks) using Ursodeoxycholic acid (UDCA) as a reference anti-fibrotic product. SCCWE at two doses (50 and 100 mg/kg) significantly ameliorated the rise in serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma glutamide transferase (GGT) activities, total bilirubin and direct bilirubin, increased total protein and albumin. SCCWE significantly reduced glutathione depletion (GSH), Nitric oxide (NOx) and malondialdehyde (MDA), thioredoxin (Trx) contents and elevated nuclear factor erythroid 2–related factor 2 (Nrf-2) content. Its anti-inflammatory effects were confirmed by observing a decrease in nuclear factor-κB (NF- κβ), interleukin-1b (IL-1β) and inducible nitric oxide synthase (iNOS) content. The anti-fibrotic effects of SCCWE were explored by assessing fibrosis related markers as it significantly reduced transform growth factor-β (TGF-β) and autotaxin (ATX) contents. Administration of SCCWE significantly decreased matrix metalloproteinase-3 and 9 (MMP-3 and -9). Furthermore, it also decreased alpha smooth muscle actin (α-SMA) and caspase-3 as assessed immunohistochemically those results were similar to that of the standard drug UDCA. This study shows that SCCWE protects against TAA-induced liver fibrosis in rats, through attenuating oxidative stress, and inflammation, ameliorating MMPs, combating apoptosis and thereby fibrotic biomarkers in addition to improving histopathological changes.

Vinpocetine attenuates thioacetamide-induced liver fibrosis in rats.

Liver fibrosis is associated with increased mortality and morbidity. However, there is not effective treatment so far. Vinpocetine (Vinpo) is a synthetic derivative of vinca alkaloid vincamine. Limited previous reports have shown some beneficial effects of Vinpo in different organ fibrosis, but the ability of Vinpo to inhibit liver fibrosis induced by thioacetamide (TAA) has not been reported, that is why we investigate the potential ability of this vinca alkaloid derivative to attenuate liver fibrosis. Hepatic fibrosis was induced in male Sprague Dawley rats by TAA (200 mg/kg; ip; 3 times/week) for 6 weeks. Daily treatments with Vinpo (10-20 mg/kg/day; orally) ameliorated TAA-induced hepatic oxidative stress and histopathological damage as indicated by a decrease in liver injury markers, LDH, hepatic MDA, and NOx levels, as well as increase anti-oxidative parameters. Besides, the anti-fibrotic efficacy of Vinpo was confirmed by decreasing hydroxyproline, and α-SMA. Also, the anti-inflammatory effect of Vinpo was explored by decreasing IL-6 and TNF-α levels. Our novel findings were that Vinpo decreased VEGF/Ki-67 expression in the liver confirming its effect on angiogenesis and proliferation. These findings reveal the anti-fibrotic effect of Vinpo against TAA-induced liver fibrosis in rats, and suggest the modulation of oxidative stress, inflammation, angiogenesis and proliferation as mechanistic cassette underlines this effect.

Combination of pomegranate extract and curcumin ameliorates thioacetamide-induced liver fibrosis in rats: impact on TGF-β/Smad3 and NF-κB signaling pathways

Protection against liver injury and its consequences is considered an essential issue to minimize the number of annual deaths caused by liver diseases. The present study was designed to evaluate the potential role of pomegranate extract (PE) and/or curcumin in the regression of thioacetamide (TAA)-induced liver fibrosis, focusing on their modulatory effects on Nrf2/HO-1, NF-κB, and TGF-β/Smad3 signaling pathways. Liver fibrosis was induced in male Wistar rats by intraperitoneal injection of TAA (100 mg/kg) three times a week, for 8 weeks. To assess the protective effects of PE and/or curcumin against TAA-induced liver fibrosis, rats were treated on a daily basis with oral doses of PE (200 mg/kg) and/or curcumin (200 mg/kg) for 8 weeks. The results indicated that PE and/or curcumin attenuated TAA-induced liver fibrogenesis, as evidenced by a significant improvement in the liver function tests (AST, ALT, ALP, and albumin), oxidative stress biomarkers (MDA, SOD, and GSH), and inflammatory biomarkers (NF-ĸB, TNF-α, IL-1β, iNOS, TGF-β, and MPO), compared to TAA group. Moreover, treatment with PE and/or curcumin exerted a significant upregulation of Nrf2/HO-1 gene expressions along with significant downregulation of NF-ĸB, TGF-β, and phospho-Smad3 protein expressions, as well as α-SMA and collagen-1 gene expressions. The histopathological examination has corroborated these findings. In conclusion, hepatoprotective activities of PE and/or curcumin could be linked to their abilities to modulate Nrf2/HO-1, NF-κB, and TGF-β/Smad3 signaling pathways. It is worth noting that the combination of PE and curcumin exerted superior hepatoprotective effects against TAA-induced liver fibrosis, as compared to monotherapy.

Hepatoprotective Effect of Probiotic Lactic Acid Bacteria on Thioacetamide-Induced Liver Fibrosis in Rats

Hepatic fibrosis is a reversible wound-healing response characterized by the accumulation of extracellular matrix. Probiotics have been used to prevent and treat various disorders. The aim of the present study was to investigate the hepatoprotective effects of probiotic lactic acid bacteria (mixture of Lactobacillus paracasei, Lactobacillus casei, and Weissella confusa) on thioacetamide (TAA)-induced liver fibrosis in rats. Thirty-five male Wistar rats were randomly divided into five groups: (1) control, (2) TAA, (3) TAA+probiotics, (4) TAA+silymarin, and (5) probiotics. Group 1 rats received a standard diet. In groups 2-4, fibrosis was induced by intraperitoneal injection of TAA (200mg/kg BW) 3 times weekly for 8 consecutive weeks. Group 4 received TAA plus 100mg/kg BW of silymarin 2 times weekly. Groups 3 and 5 were fed 109CFU/mL viable microbial cells daily by gavage. The rats were sacrificed after 8weeks of treatment. Liver tissues were collected immediately and processed for histopathological, lipid peroxidation, and Western blot analyses of TNF-α, TGF-β1, and α-SMA. Blood serum was collected to measure liver enzymes. Rats in the TAA groups suffered from hepatic injury (increased serum enzyme levels, liver inflammation, and increased concentration of TNF-α, TGF-β1, and α-SMA proteins) and extensive liver fibrosis. In contrast, TAA-treated rats receiving probiotics or silymarin had significantly lower serum enzyme levels, less inflammation, and less fibrosis. Liver damage was lower in the TAA+probiotics-treated group. Consumption of a mixture of probiotic lactic acid bacteria attenuates the development of liver fibrosis.

Effect of nanopolysaccharide (BSEPS) from Bacillus subtilis sp. on thioacetamide-induced liver fibrosis in rats

BackgroundNanomedicine contributes to the efficiency of pharmacological treatments and progresses rapidly. The present study was designed to produce exopolysaccharide (BSEPS) from Bacillus subtilis sp. strain reported in our previous study was further characterized, and its BSEPS for synthesis of the nanoparticle Ag-BSEPS using microwave heating to determine the possible effects of a prepared solution containing Ag-BSEPS versus thioacetamide (TAA) evoked liver fibrosis in Wister albino rats. Nanoparticles with silver (Ag) core have been synthesized in an aqueous solution after exposure of BSEPS to periodate oxidation. Animals were split into four groups: I - control rats, water ad libitum for 6 weeks; II - rats were injected with TAA 200 mg/kg-1 3 times/week for 4 weeks IP; III - Ag-BSEPS 100 mg/kg-1 IP twice a week for 6 weeks; and IV - TAA, as group II followed by Ag-BSEPS as group III. The antifibrotic effects of Ag-BSEPS were appraised by determining different hepatotoxicity indices, oxidative stress, and inflammatory and liver fibrosis markers.ResultsNanoparticles were obtained with a diameter size range of 50–100 nm characterized by SEM and TEM without using any harmful reagents. Results evinced considerably reduced activity of liver functions such as transaminases (AST, ALT), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP) in the group which received TAA followed by Ag-BSEPS compared to the other group which received only TAA. In the current results, the administration of Ag-BSEPS showed an improvement in the proinflammatory cytokines. On the contrary, the antioxidant enzymes in liver homogenates revealed significant improvement (concentration of glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), and catalase (CAT) increases) in animals with TAA-induced liver damage followed by Ag-BSEPS. Moreover, the activities of the fibrotic markers transforming growth factor-beta 1(TGF-β1) and type III pro-collagen (PCIII) were increased in liver tissues in the group which was given TAA alone as compared to the controls. The percentage of fibrosis of hepatic tissue had a positive correlation with the levels of PCIII and TGF-β1, followed by Ag-BSEPS compared to the TAA group without nanocomposite treatment. Microscopic examinations revealed inhibitory effects of Ag-BSEPS on inflammatory changes and deterrent of liver fibrosis.ConclusionIt was suggested that the biochemical and histological amelioration observed in Ag-BSEPS (100 mg/kg-1 twice a week for 6 weeks) treated the fibrotic rats.

The dual PPAR-α/γ agonist saroglitazar ameliorates thioacetamide-induced liver fibrosis in rats through regulating leptin.

Liver fibrosis is a challenging global health problem resulting from chronic liver injury with no treatment currently available. It has been shown that activators for different peroxisome proliferator-activated receptor (PPAR) isoforms (α, γ, and δ) can affect different pathways in liver fibrosis. To evaluate the effects of the dual PPAR-α/γ agonist saroglitazar (SGZ) against thioacetamide (TAA)-induced fibrosis in rats, SGZ was administered for 6weeks together with TAA injection. Administration of SGZ ameliorated TAA-induced elevation in hepatic biomarkers. SGZ was able to inhibit periportal and intralobular fibrous connective tissue proliferation, to decrease hydroxyproline content, and to lower alpha smooth muscle actin (α-SMA) protein expression. To unearth the antifibrotic mechanism of SGZ, the role of several fibrotic markers was studied. SGZ possesses inhibitory effect on protein levels of leptin, transforming growth factor-beta 1 (TGF-β1) and platelet-derived growth factor-BB (PDGF-BB). Furthermore, SGZ rectified matrix degradation through decreasing tissue inhibitor of metalloproteinases-1 (TIMP-1). This study suggests that SGZ could have a possible antifibrotic effect via suppression of leptin that can repress TGF-β1 and PDFG-BB, with subsequent inhibition of TIMP-1.

The anti-inflammatory and anti-fibrotic effects of tadalafil in thioacetamide-induced liver fibrosis in rats.

Liver fibrosis is a health concern that leads to organ failure mediated via production of inflammatory cytokines and fibrotic biomarkers. This study aimed to explore the protective effect of tadalafil, a phosphodiesterase-5 inhibitor, against thioacetamide (TAA)-induced liver fibrosis. Fibrosis was induced by administration of TAA (200 mg/kg, i.p.) twice weekly for 6 weeks. Serum transaminases activities, liver inflammatory cytokines, fibrotic biomarkers, and liver histopathology were assessed. TAA induced marked histopathological changes in liver tissues coupled with elevations in serum transaminases activities. Furthermore, hepatic content of nitric oxide and tumor necrosis factor-alpha, interleukin-6, and interleukin-1 beta were elevated, together with a reduction of interleukin-10 in the liver. In addition, TAA increased hepatic contents of transforming growth factor-beta, hydroxyproline, alpha-smooth muscle actin, and gene expression of collagen-1. Pretreatment with tadalafil protected against TAA-induced liver fibrosis, in a dose-dependent manner, as proved by the alleviation of inflammatory and fibrotic biomarkers. The effects of tadalafil were comparable with that of silymarin, a natural antioxidant, and could be assigned to its anti-inflammatory and anti-fibrotic properties.

Retracted: PASS-Predicted Hepatoprotective Activity of Caesalpinia sappan in Thioacetamide-Induced Liver Fibrosis in Rats.

[This retracts the article DOI: 10.1155/2014/301879.].

Antioxidant and Hepatoprotective Effects of Tranilast against Thioacetamide-Induced Liver Fibrosis in Rats

The aim of the present study was to investigate the potential antioxidant and Hepatoprotective activities of tranilast against TAA-induced liver fibrosis in rats. Methods: Liver fibrosis was induced in rats by intra peritoneal injection of TAA (200 mg/kg) for 6 weeks. Tranilast was administered orally at a dose of 150 and 300mg/kg for 6 weeks before induction of liver fibrosis. Results: Injection of TAA induced hepatic fibrosis that was manifested by a significant increase in the activities of aminotransferases and total bilirubin with a significant decrease in total protein and albumin in serum. Liver homogenate of TAA rats had the lower content of reduced glutathione (GSH) and superoxide dismutase (SOD) with increased levels of the hepatic malondialdehyde. Histological data presented marked damage in liver sections of TAA rats. Oral dosing of tranilast for 6 weeks before induction of liver fibrosis reversed these altered parameters near to normal values. These results suggest that tranilast could afford significant protection and antioxidant effect in prevention of liver fibrosis.

Naringin attenuates thioacetamide-induced liver fibrosis in rats through modulation of the PI3K/Akt pathway

AimsNaringin (NR) is a flavanone glycoside extracted from grapefruits and citrus fruits. The aim of this study is to investigate the antifibrotic efficacy of NR in thioacetamide (TAA)-induced hepatic fibrosis in rats through evaluating NR effect on the PI3K/Akt pathway. Main methodsHepatic fibrosis was induced in rats by intraperitoneal injection of TAA (200mg/kg) twice per week for 6weeks. Simultaneously, NR (40mg/kg/day, p.o.) was given along with TAA injection. The ratio of P-Akt/Akt was assessed in hepatic homogenate as well as antioxidant enzymes (catalase, superoxide dismutase (SOD), glutathione peroxidase (GPx)) and lipid peroxidation marker, malondialdehyde (MDA). Serum level of interleukin (IL)-6 were measured using ELISA. Hepatic tissues were examined histopathologically using hematoxylin and eosin (H&E) and Masson trichome staining. Tissue expression of alpha smooth muscle actin (α-SMA), transforming growth factor β1 (TGF-β1), caspase-3 and fibronectin were scored immunohistochemically. Finally, the mRNA level of cytokine genes (IL-1β, IL-6, IL-10, interferon gamma (IFN-γ)), caspase-3, TGF-β1 and fibronectin were quantified using qPCR. Key findingsNR significantly suppressed Akt phosphorylation associated with increased number of caspase-3 positive cells especially in the fibrotic areas. Liver tissues of treated rats showed restoration of normal liver histology and decrease in collagen and fibronectin deposition. Furthermore, NR treatment ameliorated oxidative stress and inflammatory cytokine production. SignificanceNR alleviated experimental liver fibrosis through inhibition of PI3K/Akt pathway beside its anti-inflammatory and antioxidant effects. Therefore, NR is a promising therapeutic candidate for hepatic fibrosis.

Hepatoprotective effects of naturally fermented noni juice against thioacetamide-induced liver fibrosis in rats

BackgroundExcessive reactive oxygen species (ROS) can result in inflammation and cytokine secretion in the liver, and then activate hepatic stellate cells that cause the accumulation of extracellular matrix proteins, especially collagen, in liver tissue. Naturally fermented noni juice (NJ; Morinda citrifolia) has been used for decades as a nutraceutical in humans. In this study, we intended to examine if NJ can ameliorate ROS-induced liver fibrosis via a thioacetamide (TAA)-induced rat model. MethodsThe 50 rats used in this study were separated into five groups of 10 rats each for 8 weeks as follows: (1) control group; (2) TAA; (3) TAA+low-dose NJ (2.51 mL NJ/kg); (4) TAA+medium-dose NJ (5.02 mL NJ/kg); and (5) TAA+high-dose NJ (7.52 mL NJ/kg). ResultsTreatment with TAA resulted in lower body weight and serum lipid levels (p<0.05), while liver weight and collagen contents, and serum alanine aminotransferase and aspartate aminotransferase values were increased (p<0.05). The protective effects of NJ on TAA treatment resulted from decreased endoplasmic reticulum stress-related gene expressions (p<0.05), inflammatory cytokines, collagen accumulation, and matrix metalloproteinase (MMP-2 and MMP-9) activities, as well as upregulated (p<0.05) tissue inhibitors of metalloproteinase (TIMP-1 and TIMP-3) in livers. NJ also increased hepatic antioxidant capacities (p<0.05). ConclusionNaturally fermented NJ manifests a protective potential on liver fibrosis via the enhancement of antioxidant capacities, as well as decreasing endoplasmic-reticulum stress and MMP-2/MMP-9 activities.