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Tropical Journal of Natural Product Research Hepatocurative Effects of Alpha Lipoic Acid in 5-Fluorouracil-Induced Toxicity Involves Activation of TNF Alpha and NF-κβ Signaling Pathway
Abstract and Figures
Alpha Lipoic Acid is an antioxidant capable of inhibiting xenobiotic-induced liver toxicity as reported in adriamycin-induced hepatotoxicity in rats. The present research was designed to study the hepatocurative effects of Alpha Lipoic acid(ALA) in 5-fluorouracil(5-FU) induced hepatotoxicity of wistar rats. Intraperitoneal injection of 50 mgkg-1 of 5-FU was associated with significant (p≤0.05) increase in the Phenobarbital-induced sleeping time, NF-κB, TNF-α, AST,ALP, ALT, triglyceride,cholesterol and LDL levels in the toxicity control when compared with untreated control rats. However, intraperitoneal injection of 50 mgkg-1 of 5-FU was associated with significant (p≤0.05) decrease albumin, total protein, HDL levels in the toxicity control when compared with Negative control rats.Daily oral post-treatment with 400 mgkg-1 ALA after 5-FU injection non-significantly (p˃0.05) attenuated increase in the HDL level when compared to the Negative control group.Intraperitoneal injection of 50 mgkg-1 of 5-FU was associated with remarkable necrosis when compared to normal liver architecture. Daily oral post-treatment with 400 mgkg-1 ALA after 5-FU injection significantly (p≤0.05) attenuated these trends.ALA has hepatocurative potential in 5-FU-induced hepatotoxicity of wistar rats.
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The present study investigates the hepatoprotective and antioxidant activity of alpha lipoic acid (ALA) on carbamazepine (CBZ) administered rats. 30 animals were divided into 5 groups. Animals in group 1 received drinking water orally and served as control, group 2 received CBZ 50 mg/Kg dissolved in water daily by oral gavage, group 3, 4 and 5 received (50, 100 and 200 mg/Kg) of ALA in 0.2% carboxy methyl cellulose respectively 1 hr prior to administration of 50 mg/Kg CBZ for a duration of 45 days. The levels of serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), alkaline phosphatase, bilirubin, albumin and total protein were estimated to determine the hepatoprotective activity. The levels of superoxide dismutase (SOD), glutathione (GSH), catalase and lipid peroxidation levels were estimated to determine the antioxidant activity. Histopathological examination was also done. CBZ increased the level of SGOT, GSH, catalase and increased lipid peroxidation. Administration of ALA reversed the CBZ induced hepatotoxicity. Histopathological examination revealed preservation of liver integrity in ALA administered rats compared to CBZ alone treated rats. The hepatoprotective effect of ALA was due to its antioxidant activity by scavenging free radicals.
Background/aims:
The clinical utility of 5-fluorouracil (5-FU) is limited by its nephrotoxicity. Camel milk (CM) has previously displayed beneficial effects in toxicant-induced nephropathies. The current study aimed to investigate the potential of CM to attenuate 5-FU-induced nephrotoxicity in rats.
Methods:
Renal tissues were studied in terms of oxidative stress, inflammation and apoptosis. The levels of renal injury markers, inflammatory cytokines along with NOX-1, Nrf-2 and HO-1 were assessed by ELISA. The expression of MMP-2, MMP-9, NF-κBp65, p53, Bax and PCNA were detected by Immunohistochemistry. To gain an insight into the molecular signaling mechanisms, we determined the effect of CM on MAPKs, NF-κB and PI3K/Akt/eNOS pathways by Western blotting.
Results:
CM lowered 5-FU-triggered increase of creatinine, BUN, Kim-1 and NGAL renal injury biomarkers and attenuated the histopathological aberrations. It suppressed oxidative stress and augmented renal antioxidant armory (GSH, SOD, GPx, TAC) with restoration of NOX-1, Nrf-2 and HO-1 levels. CM also suppressed renal inflammation as indicated by inhibition of MPO, TNF-α, IL-1β, IL-18 and MCP-1 proinflammatory mediators and downregulation of MMP-2 and MMP-9 expression with boosting of IL-10. Regarding MAPKs signaling, CM suppressed the phosphorylation of p38 MAPK, JNK1/2 and ERK1/2 and inhibited NF-κB activation. For apoptosis, CM downregulated p53, Bax, CytC and caspase-3 proapoptotic signals with enhancement of Bcl-2 and PCNA. It also enhanced PI3K p110α, phospho-Akt and phospho-eNOS levels with augmentation of renal NO, favoring cell survival. Equally important, CM preconditioning enhanced 5-FU cytotoxicity in MCF-7, HepG-2, HCT-116 and PC-3 cells, thus, justifying their concomitant use.
Conclusion:
The current findings pinpoint, for the first time, the marked renoprotective effects of CM that were mediated via ROS scavenging, suppression of MAPKs and NF-κB along with activation of PI3K/Akt/eNOS pathway.
and nephrotoxicity. The study objective was to investigate the protective effects of naringin on 5-FUinduced
hepatotoxicity and nephrotoxicity.
Materials and Methods: Thirty rodents were assigned to three groups. The control group received
1 ml of intragastric distilled water for 14 days. The 5-FU group received 1 ml of distilled water for
14 days as a placebo. On day 9, this same group received a 20 mg/kg dose of 5-FU administered
intraperitoneally(IP) for a further five days. The naringin+5-FU group received a 100 mg/kg dose of
naringin (IP) for 14 days. On day 9, 20 mg/kg of 5-FU was administered (IP) to this group for a further
five days. On day 15, the rats were decapitated, and blood and renal and hepatic tissues were taken.
Results: It was determined that serum creatinine, BUN, AST, ALT, ALP, and LDH levels, as well as
cytokine levels in the liver and kidney tissues were significantly elevated in the 5-FU group, compared
to the control group. The comparative values were similar in the control and naringin+5-FU groups.
When the liver tissue was examined histopathologically, in the control group it was found to be normal
in structure. However, necrosis was observed in the hepatocytes of the pericentric region in the 5-FU
group. 8-OHdG cell density was significantly elevated in the 5-FU group, compared to the control and
naringin+5-FU groups.
Conclusion: Naringin was observed to have a protective effect on 5-FU-induced liver and kidney
damage.
Objective: To investigate the effects of quercetin (Q) and rutin on 5-fluorouracil (5-FU)-induced hepatotoxicity. Methods: The control group was corn oil. The 5-FU group rats were corn oil and injected intraperitoneal 5-FU 50 mg/kg. Groups rutin 50 + 5-FU and rutin 100 + 5-FU were respectively 50 mg/kg and 100 mg/kg rutin. These groups were given 5-FU (50 mg/kg) in the 18th day. The group rutin 100 was rutin (100 mg/kg i.g.). Groups Q50 + 5-FU and Q100 + 5-FU were respectively 50 mg/kg and 100 mg/kg quercetin. These groups were given 5-FU (50 mg/kg) in the 18th day of quercetin application. The group Q100 was quercetin (100 mg/kg i.g.). In the end of experimental applications, blood was collected from anesthetized rats. Results: The MDA level was significantly higher in the 5-FU group compared with control group, and determined to be decreased in other groups. GPx and GSH levels were significantly decreased in the 5-FU group compared to the control, rutin 100 + 5-FU and Q100 + 5-FU groups. AST, ALT, LDH and ALP levels in the serum were significantly increased in the 5-FU group compared with the other groups. The results from this analysis show that while the caspase-3 level increases in the 5-FU group, it decreases in the Q50 + 5-FU, Q100 + 5-FU, rutin 50 + 5-FU and rutin 100 + 5-FU groups. Bcl-2 level decreased in the 5-FU group compared to the control group, but increased in the rutin 100 + 5-FU, Q50 + 5-FU and Q100 + 5-FU groups. Conclusions: In this study it was determined that the rutin and Q have protective effects on 5-FU-induced hepatotoxicity.
5-Fluorouracil (5-FU) is a pyrimidine analogue that is used as an anti-cancer drug but its therapeutic potential is limited by its hepatotoxicity. This study therefore, aimed at investigating the protective effect of crocin, a natural supplement, against 5-FU-induced liver injury. Male rats were administered with 5-FU (30 mg/kg b.wt i.p.) for 5 days. Two groups of animals were either orally treated 3 days prior to or 3 days after 5-FU administration with crocin (40 mg/kg bwt). Another group was concurrently treated with crocin along with 5-FU administration. Biochemical variables indicative of liver injury, oxidative stress and liver histopathological alterations were thereafter determined. 5-FU administration markedly increased oxidative stress and markers of hepatic injury. Pre-, concurrent and post-treatment with crocin significantly reduced MDA, AOPP and LOOH levels and increased total antioxidant capacity compared to the 5-FU alone group, with improvement in the activities of the antioxidant enzymes, SOD, CAT and PONase. Liver injury was markedly reversed when AST, ALT and ALP activities estimated in the three treatment groups were compared to 5-FU group, but the restoration was incomplete, compared to the control. These biochemical variables were supported by histopathological examinations. The results indicate that crocin supplementation can ameliorate 5-FU-induced oxidative stress and liver injury in rat.
Oxidative stress is thought to be a key risk factor in the development of hepatic diseases. Blocking or retarding the reactions of oxidation and the inflammatory process by antioxidants could be a promising therapeutic intervention for prevention or treatment of liver injuries. Oligonol is a low molecular weight polyphenol containing catechin-type monomers and oligomers derived from lychee fruit. In this study, we investigated the anti-inflammatory effect of oligonol on carbon tetrachloride- (CCl
4
-) induced acute hepatic injury in rats. Oral administration of oligonol (10 or 50 mg/kg) reduced CCl
4
-induced abnormalities in liver histology and serum AST and serum ALT levels. Oligonol treatment attenuated the CCl
4
-induced production of inflammatory mediators, including TNF-
α
, IL-1
β
, cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) mRNA levels. Western blot analysis showed that oligonol suppressed proinflammatory nuclear factor-kappa B (NF-
κ
B) p65 activation, phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun NH
2
-terminal kinase (JNK), and p38 mitogen-activated protein kinases (MAPKs) as well as Akt. Oligonol exhibited strong antioxidative activity
in vitro
and
in vivo
, and hepatoprotective activity against
t
-butyl hydroperoxide-induced HepG2 cells. Taken together, oligonol showed antioxidative and anti-inflammatory effects in CCl
4
-intoxicated rats by inhibiting oxidative stress and NF-
κ
B activation via blockade of the activation of upstream kinases including MAPKs and Akt.
BACKGROUND:
Flavonoids and other polyphenols play a protective role in liver diseases and possess a high antioxidant capacity.
OBJECTIVE:
To compare and evaluate the antioxidant and hepatotoprotective activities of 4 deserts plants, Fagonia indica Burm. f., Calotropis procera R.Br., Zygophylum hamiense Schweinf. and Salsola imbricata Forssk. in correlation to their composition especially their phenolic content.
METHODS:
The influence of extracting solvent on total phenolic and flavonoidal contents was assessed spectrophotometrically. The flavonoid and other polyphenolic components of the methanol extracts were analyzed by RP-HPLC. DPPH radical scavenging potential of the different extracts was estimated. The hepatoprotective and antioxidant activities of the extracts against CCl4-induced hepatotoxicity in mice were evaluated.
RESULTS:
The flavonol quercitrin and rosmarinic acid were major in the F. indica, C. procera and S. imbricata samples, while rutin prevailed in that of Z. hamiense. The ethanolic and methanolic extracts showed noticeable DPPH radical-scavenging activity as compared to ascorbic acid. Assessment of liver enzymes revealed that oral administration of the extracts did not show any evidence of hepatotoxicity. Moreover, protection against CCl4-induced liver damage was evident upon administration of three plants extracts namely, F. indica, C. procera and S. imbricata.
CONCLUSION:
Overall, hepatotoxicity induced by CCl4 was effectively prevented by the three plants extracts through scavenging of free radicals and by boosting the antioxidant capacity of the liver. The protective effect of the plants could be attributed to their high quercitrin and rosmarinic acid contents.
Alpha-lipoic acid (α-LA) is not only involved in energy metabolism, but is also a powerful antioxidant that can protect against hepatic oxidative stress induced by some drugs, toxins, or under various physiological and pathophysiological conditions. Here, we investigated the effect of α-LA against liver oxidative damage in broilers exposed to aflatoxin B1 (AFB1). Birds were randomly divided into four groups and assigned different diets: basal diet, 300 mg/kg α-LA supplementation in basal diet, diet containing 74 μg/kg AFB1, and 300 mg/kg α-LA supplementation in diet containing 74 μg/kg AFB1, for 3 weeks. The results revealed that the addition of 300 mg/kg α-LA protected against the liver function damage of broilers induced by chronic low dose of AFB1 as estimated by a significant (p<0.05) change in levels of plasma total protein, albumin, alkaline phosphatase and the activities of liver glutamic-oxalacetic transaminase and glutamic-pyruvic transaminase. The histopathological analysis also showed that liver tissues were injured in the AFB1 diet, but this effect was alleviated by the addition of 300 mg/kg α-LA. Additionally, AFB1 induced a profound elevation of oxidative stress in birds, as indicated by an increase in malondialdehyde level, a decrease in glutathione peroxidase activity and a depletion of the glutathione content in the liver. All of these negative effects were inhibited by treatment with α-LA. Our results suggest that the inhibition of AFB1-induced excess production of lipid peroxides and the maintenance of intracellular antioxidant status may play important roles in the protective effects of α-LA against AFB1-induced oxidative damage in the liver.
Background:
In mammals lipoic acid (LA) and its reduced form dihydrolipoic acid (DHLA) function as cofactors for multienzymatic complexes catalyzing the decarboxylation of α-ketoacids. Moreover, LA is used as a drug in a variety of diseases including inflammatory diseases. The aim of the study was to examine anti-inflammatory properties of LA metabolites.
Material/methods:
The present paper reports the chemical synthesis of 2,4-bismethylthio-butanoic acid (BMTBA) and tetranor-dihydrolipoic acid (tetranor-DHLA). BMTBA is one of the biotransformation products of LA, while tetranor-DHLA is an analogue of DHLA. Structural identity of these compounds was confirmed by 1H NMR. These compounds were assessed for their anti-inflammatory activity in mice. For this purpose, the zymosan-induced peritonitis and the carrageenan-induced hind paw edema animal models were applied.
Results/conclusions:
The obtained results indicated that the early vascular permeability measured at 30 min of zymosan-induced peritonitis was significantly inhibited in groups receiving BMTBA (10, 30, 50 mg/kg). The early infiltration of neutrophils measured at 4 hours of zymosan-induced peritonitis was inhibited in the group receiving BMTBA (50 mg/kg) and tetranor-DHLA (50 mg/kg). The results indicated that the increase in paw edema was significantly inhibited in the groups receiving BMTBA (50, 100 mg/kg) and tetranor-DHLA (30, 50 mg/kg). In summary, the present studies clearly demonstrated that both BMTBA and tetranor-DHLA were able to act as anti-inflammatory agents. This is the first study examining in vivo the anti-inflammatory properties of LA metabolites.