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Parkin deficiency prevents chronic ethanol-induced hepatic lipid accumulation through β-catenin accumulation

Parkin deficiency prevents chronic ethanol-induced hepatic lipid accumulation through β-catenin accumulation

Parkin is an E3 ubiquitin ligase expressed in several organs and multiple substrates have been identified [15]. Rawal et al. reported that parkin interacts with β-catenin and protects against cell death by excessive β-catenin signaling through β-catenin degradation in neuronal cells [23]. However, the function of parkin in hepatic lipid accumulation through interaction with β-catenin has not been studied. In several studies, β-catenin was closely associated with hepatic metab- olism and hepatocellular energy balance. Behari et al. re- ported that liver-specific β-catenin knockout mice exhibit increased susceptibility to diet-induced hepatosteatosis [11]. Liver-specific β-catenin knockout mice also show abnormal bile canalicular morphology, low bile flow rates and intrahe- patic cholestasis [37]. Furthermore, Liu et al. reported that β-catenin knockout mice develop severe hepatosteatosis after ethanol consumption [12]. Ethanol-induced β -catenin knockout mice exhibit abnormal mitochondrial function and down-regulation of genes involved in fatty acid β-
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Ethanol-induced oxidative stress: basic knowledge

Ethanol-induced oxidative stress: basic knowledge

That ethanol-induced liver changes are in part mediated by the proximal metabolite acetaldehyde that has been pro- posed since a long time ago and reconsidered when it has been observed [21] that many of the earlier mentioned ethanol-induced mitochondrial changes are reproduced by acetaldehyde. In particular, the addition of acetaldehyde to isolated mitochondria at concentrations of the same order as those occurring in the liver actively oxidizing ethanol (1–3 mM), inhibits mitochondrial respiration at the level of complex I (NADH-ubiquinone oxido-reductase) and the coupling site I of oxidative phosphorylation [21, 22]. Moreover, acetaldehyde inhibits, at the same concentra- tions, fatty acid oxidation, and such inhibition seems to be due to the inhibition of b-oxidation, citric acid cycle and oxidative phosphorylation [24]. The inhibition of the oxidation of NAD ? -dependent substrates [21] and the inhibition of fatty acid oxidation [24] do not seem to depend from a competition of acetaldehyde with such substrates for NAD ? . It has been suggested [23, 25], on the other hand, that acetaldehyde could interact with sul- phydryl groups involved in oxidative phosphorylation particularly with those essential for the complex I (NAD ? ubiquinone-oxydoreductase) which is the site of the respiratory chain mainly affected by both acetaldehyde and ethanol. Thus, the block of –SH groups would be responsible for the alterations. The reaction of acetalde- hyde and other alkanals with cysteine has been actually known since many decades (formation of thiazolidine- carboxylic acids) and other low molecular weight thiols (reduced glutathione, GSH, in particular) can also be involved in this reaction. In effect, ethanol toxicity is always accompanied by a decrease in hepatic GSH con- tent. If, as we will see later, lipid peroxidation is going to develop in ethanol hepatotoxicity, much more reactive aldehydes (alkenals and 4-hydroxyalkenals) will be formed and a much higher reactivity toward –SH groups and other nucleophiles has to be expected.
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Effects of pithecellobium jiringa ethanol extract against ethanol induced gastric mucosal injuries in Sprague Dawley rats

Effects of pithecellobium jiringa ethanol extract against ethanol induced gastric mucosal injuries in Sprague Dawley rats

respectively. Sixty minutes later, vehicle was given orally to the normal control group, and absolute ethanol was given orally to the ulcer control, positive control and experimental groups to generate gastric mucosal injury. The rats were sacrificed an hour later. The effect of oral administration of plant extract on ethanol-induced gastric mucosal injury was studied grossly and histology. The level of lipid peroxidation, (malondialdehyde—MDA), superoxide dismutase (SOD) and gastric wall mucus were measured from gastric mucosal homogenate. The ulcer control group exhibited severe gastric mucosal injury, and this finding was also confirmed by histology of gastric mucosa which showed severe damage to the gastric mucosa with edema and leucocyte infiltration of the submucosal layer. Pre-treatment with plant extract significantly reduced the formation of ethanol-induced gastric lesions, and gastric wall mucus was significantly preserved. The study also indicated a significant increase in SOD activity in gastric mucosal homogenate, whereas a significant decrease in MDA was observed. Acute toxicity tests did not show any signs of toxicity and mortality up to 5 g/kg. The ulcer protective effect of this plant may possibly be due to its preservation of gastric wall mucus along with increased SOD activity and reduction of oxidative stress (MDA). The extract is non-toxic, even at relatively high concentrations.
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Microglial-derived miRNA let-7 and HMGB1 contribute to ethanol-induced neurotoxicity via TLR7

Microglial-derived miRNA let-7 and HMGB1 contribute to ethanol-induced neurotoxicity via TLR7

media MV followed by RT-PCR for miR let-7b. Ethanol was found to increase the association of let-7b with HMGB1 in MVs by 50% (Fig. 5a). Concomitantly, etha- nol reduced the association of let-7b with its classical chaperone protein argonaute (Ago2) [37] in microvesi- cles by approximately 50% (Fig. 5b). In order to deter- mine if this ethanol effect showed specificity for let-7b, we assessed two additional relevant pro-inflammatory miRNAs, miR-155 and miR181c. The miR-155 has been shown previously to be increased by 2.5-fold in plasma MVs in response to ethanol [24]. HMGB1 binding to miR181c was non-detectable after ethanol treatment (not shown). We found that ethanol increases miR-155 levels by 6.7-fold in our MV preparations (100 nm– 1 μm) from BV2 microglia (Fig. 5c). Ethanol did not, however, increase the binding of HMGB1 with miR-155 (not shown), though miR-155 binding to Ago2 binding was increased as expected (Fig. 5f). Thus, ethanol is alter- ing miRNA-chaperone binding in MVs. Ethanol-induced increases in let-7b binding to HMGB1 appear to be unique from other ethanol-induced miRNAs. This could be associated with the targeting of miRNA to MVs for se- cretion rather than to the RISC complex for regulation of mRNA stability and should be investigated in future stud- ies. Regardless, ethanol increased HMGB1-let-7b com- plexes in MVs released from HEC brain slices.
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Hepatoprotective Activity of Cochlospermum Religiosum Leaves Extract against CCl4 and Ethanol Induced Hepatic Damage in Rats

Hepatoprotective Activity of Cochlospermum Religiosum Leaves Extract against CCl4 and Ethanol Induced Hepatic Damage in Rats

Abstract: Liver disease is one of the fatal diseases. Medicinal plants may serve as one of the best sources of remedies for treatment of liver disease. Identification of a potential therapeutic agent for protection of liver from hepatotoxins provides a useful way for the prevention of liver related illnesses. Effect of Cochlospermum religiosum leaves aqueous and ethanolic extracts were studied on CCl 4 and ethanol induced hepatic damage in rats. Cochlospermum religiosum was found to protect the

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GASTROPROTECTIVE EFFECT OF ABRUS PRECATORIUS ON ETHANOL INDUCED AND ASPIRIN + PYLORUS LIGATION INDUCED PEPTIC ULCER IN RATS

GASTROPROTECTIVE EFFECT OF ABRUS PRECATORIUS ON ETHANOL INDUCED AND ASPIRIN + PYLORUS LIGATION INDUCED PEPTIC ULCER IN RATS

Peptic ulcer is a multifactorial disease associated with inflammation, acid induced necrosis, oxidative damage, apoptosis and loss of gastroprotection [23]. The genesis of ethanol-induced gastric lesion is of multifactorial origin with the decrease in gastric mucus amount also it is associated with significant production of free radicals leading to increased lipid peroxidation which inturn causes damage to cell and cell membranes [24]. Ethanol induced gastric lesion formation may be due to stasis in gastric blood flow which contributes to the development of the haemorrhage and necrotic aspects of tissue injury. Thus, due to gastric acid over secretion increases ulcer index [25].
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“Ginger Extract Attenuates Ethanol - Induced Oxidative Stress in Rat Small Intestine” by Jeepalem. Himabindu, Ganjikunta. Venkata Subbaiah, Sahukari. Ravi, Basha.Shanmugam, Kesireddy. Sathyavelu Reddy, India.

“Ginger Extract Attenuates Ethanol - Induced Oxidative Stress in Rat Small Intestine” by Jeepalem. Himabindu, Ganjikunta. Venkata Subbaiah, Sahukari. Ravi, Basha.Shanmugam, Kesireddy. Sathyavelu Reddy, India.

Chronic alcohol consumption can exert deleterious effects on the structures and functions of all parts of the Gastro intestinal tract (GIT). This study evaluates the protective effect of ethanol extract of ginger on ethanol-induced oxidative stress in the small intestine of rats. Oxidative stress in the intestine tissue was evaluated by estimation of the activities of superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST), glutathione reductase (GR) and glutathione peroxidation (Se-GSH-Px). In the present study GST activity was significantly (p<0.001) increased whereas GR, Se-GSH-Px, SOD and CAT activities were significantly (p<0.001) decreased in the intestine of rats treated with ethanol alone (6g/kg). Ethanol extract of ginger (200mg/kg) administration exerts a significant (p<0.001) increase in GR, Se-GSH-Px, SOD and CAT activities, a marked reduction in the GST. However, ginger administration ameliorated the effects of ethanol, suggesting that ginger is a potential antioxidant against ethanol-induced oxidative stress.
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Neuroprotection by taurine in ethanol-induced apoptosis in the developing cerebellum

Neuroprotection by taurine in ethanol-induced apoptosis in the developing cerebellum

The presence of taurine at high concentrations during the early ontogenesis is essential for normal develop- ment [37]. Taurine has been tested in treatment of many diseases, including cardiovascular disorders, epi- lepsy, macular degeneration, hepatic disorders, cystic fibrosis, Alzheimer’s disease and alcoholism [38]. It also interacts with the effects of ethanol [39]. For instance, it modulates ethanol-stimulated locomotion [40] and pro- longs ethanol-induced sedation when given intracerebro- ventricularly to mice [41,42]. Furthermore, ethanol administration elicits an increase in extracellular taurine in the rat cerebral cortex and hippocampus [43]. How- ever, many findings on taurine and ethanol interactions have been contradictory. For instance, in behavioural studies taurine pretreatment has reduced the duration of ethanol-induced sleep-time and attenuated the loss of righting reflex [44,45], not altered the ethanol-induced loss of righting reflex [46] or even enhanced it [41]. It seems that interactions of taurine and ethanol in the brain depend largely on the experimental set-up and the doses of ethanol and taurine administered [19].
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Mechanisms of ethanol-induced steroidogenesis following acute and chronic ethanol exposure

Mechanisms of ethanol-induced steroidogenesis following acute and chronic ethanol exposure

At first glance, one might presume that chronic ethanol decreases P450scc activity compared to acute ethanol because pregnenolone levels are decreased. Furthermore, StAR levels remain elevated following chronic ethanol exposure suggesting that cholesterol can still be transported to P450scc on the inner mitochondrial membrane. However, based on the present study, as well as data in the literature, it is likely that chronic ethanol exposure causes alterations in HPA axis functioning that lead to reduced steroid levels. Moreover, tolerance to HPA axis activation would diminish ACTH release and ACTH is postulated to contribute to cholesterol availability (Jefcoate, 2002). Furthermore, following repeated ethanol exposures, HPA axis activation is tolerant to an ethanol challenge but can mount a full response to a footshock (Rivier and Lee, 2001). Thus, P450scc activity seems to remain intact and the lack of an ethanol-induced steroid response appears to be due to HPA axis tolerance. Although the focus of this project was on in vivo mechanisms of adrenal steroidogenesis, future studies could take the important steps identified, such as P450scc activity, and use an in vitro system to do more in depth mechanistic studies. Indeed, some studies are underway in the lab to examine the effects of increasing P450scc enzyme expression, and presumably its activity, on neuroactive steroid levels.
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Pathogenesis and mechanisms of ethanol-induced limb defects

Pathogenesis and mechanisms of ethanol-induced limb defects

To investigate the early biological changes that occur in the limb bud following embryonic ethanol exposure, microarray analysis of transcriptional changes was conducted. To minimize detection of transcriptional adaptations that occur as a consequence of cell death or altered rates of proliferation, the present study focused on limb buds that had been exposed to ethanol for only 2, 4, and 6 hours. Previous descriptions of transcriptional changes following embryonic ethanol exposure have focused on changes in a small number of potential gene targets of ethanol (Yamada et al., 2005; Xu et al., 2005; Chrisman et al., 2004). The strength of a microarray analysis lies in the ability to simultaneously probe several hypothesized mechanisms of ethanol teratogenesis. In an effort to identify or confirm cellular and molecular targets of ethanol, functional and pathway analyses were used to assess transcriptional alterations reflecting ethanol’s early effects on metabolism, cell signaling, and cellular activity. Because of the transcriptionally distinct subpopulations of cells within the limb bud, this investigation was expected to identify ethanol-sensitive subpopulations of the limb bud that had not previously been identified as important in the pathogenesis of ethanol- induced limb defects. In addition, transcripts of specific genes known to play a role in redox regulation and response were analyzed to determine if their response would indicate an early
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CURATIVE EFFECTS OF MALOTILATE ON ETHANOL – INDUCED HEPATIC DYSFUNCTION IN RATS

CURATIVE EFFECTS OF MALOTILATE ON ETHANOL – INDUCED HEPATIC DYSFUNCTION IN RATS

Thus the synthesizing capacity of liver was hampered by ethanol. Treatment with malotilate for further 21 days effectively reversed this effect and by day-42 the total protein and albumin levels were so significantly increased that they were comparable to their baseline values whereas, no such improvement was seen in group-2 of methyl cellulose treatment. These observations confirm the restorative effect of malotilate on ethanol induced hepatic damage. Imaizumi and Kato (1981) 12 and Niwano and Katoh (1985) 13 reported restorative effect of malotilate on the liver as increase in liver weight and liver protein attributed to increase in RNA and DNA contents in the liver. Similar findings have been reported by Igarashi, Hatahara and Funaki (1983) that malotilate offers hepatotrophic action by increase in protein synthesis in hepatectomised rats 14 . These results suggest that malotilate accelerates cell proliferation, resulting in facilitation of liver regeneration in rats.
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Adenosine signaling contributes to ethanol induced fatty liver in mice

Adenosine signaling contributes to ethanol induced fatty liver in mice

Deletion of ecto-5′-nucleotidase prevents the development of ethanol-induced fatty liver in mice. Eight-week-old male mice (WT and CD73KO mice) were fed a liquid diet containing ethanol or an equal caloric diet containing maltose for 6 weeks. Mice were then sacrificed at the end of sixth week, and their livers were collected and stained with H&E and Oil Red O. The livers and bod- ies of the mice were weighed on the day of sacrifice and the liver/total body weight ratio was calculated. The serum AST and triglyc- eride and hepatic tissue triglyceride levels were also measured, as described in Meth- ods. The hepatic steatosis grade was based on the percentage of steatotic hepatocytes in the H&E-stained liver sections. (A) H&E- stained liver sections from maltose- and ethanol-treated WT and CD73KO mice (original magnification, ×400). (B) Hepatic steatosis grades of ethanol-treated WT and CD73KO mice. Steatosis grades in malt- ose-treated WT and CD73KO mice were 0. (C) Oil Red O–stained liver sections from WT and ethanol-treated WT and CD73KO mice (original magnification, × 400). (D) Liver/body weight ratio of CD73KO and WT mice. (E) Serum AST levels of WT and CD73KO mice. (F) Serum triglyceride levels of WT and CD73KO mice. (G) Hepatic tis- sue triglyceride levels in WT and CD73KO mice. # P < 0.01, CD73KO mice versus WT
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Protective effect of quercetin in the regression of ethanol-induced hepatotoxicity

Protective effect of quercetin in the regression of ethanol-induced hepatotoxicity

Alcohol induced significant lipid peroxidation (Table 3). Level of malondialdehyde was increased significantly in ethanol treated group. This was signiÞ cantly reduced by quercetin supplementation. Upon alcohol administration; there was significant increase in tissue hydroperoxide level. This was reduced signiÞ cantly by quercetin supplementation. Conjugated diene level was also found to be higher in ethanol treated group. Quercetin supplementation caused a reduction in conjugated diene level compared to abstention group. Ethanol administration resulted in significant decrease in liver glutathione content. Quercetin supplementation resulted in increase of glutathione content to a signiÞ cant level compared to normal abstention group (Table 4). After ethanol administration liver sections showed extensive hepatocellular damage as evidenced by ballooning of hepatocytes, steatosis, vacuolization and dilation of sinusoids (Þ g. 2a). The histological features of the liver in the control group showed a normal liver architecture and cell structure (Þ g. 2b). Quercetin
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Hepatoprotective activity of Maavilingapattai Chooranam on CCl4, Paracetamol and Ethanol Induced Hepatotoxicity in In-vivo models

Hepatoprotective activity of Maavilingapattai Chooranam on CCl4, Paracetamol and Ethanol Induced Hepatotoxicity in In-vivo models

The effects of Solanum nigrum (Family of Solanaceae) extract (SNE) was evaluated on thioacetamide (TAA) induced liver fibrosis in mice. Mice in the three TAA groups were treated daily with distilled water and SNE (0.2 or 1.0 g/kg) via gastrogavage throughout the experimental period. SNE reduced the hepatic hydroxyproline and αsmooth muscle actin protein levels in TAA treated mice. SNE inhibited TAA induced collagen (α1) (I), transforming growth factor-β1 (TGF-β1) and mRNA levels in the liver. Histological examination also confirmed that SNE reduced the degree of fibrosis caused by TAA treatment. Oral administration of SNE significantly reduces TAA induced hepatic fibrosis in mice, probably through the reduction of TGF-β1 secretion.
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The effects of thiamine pyrophosphate on ethanol induced optic nerve damage

The effects of thiamine pyrophosphate on ethanol induced optic nerve damage

Reactive oxygen species produced as a result of etha- nol consumption reacts with biological macromolecules such as DNA and results in the lipid peroxidation. MDA is the end product of lipid peroxidation and regarded as an indicator of measure of oxidative stress [22]. De- creased serum and tissue MDA levels determined in our study was also showing the success of thiamine pyro- phosphate in preventing oxidative stress development. Glutathione is an important non-enzymatic antioxidant decreasing lipid peroxidation in tissues [23]. We have determined significantly higher reduced glutathione levels in serum and tissues in thiamine pyrophosphate group compared with the ethanol group showing the anti-oxidant effects of thiamine pyrophosphate. We also
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STUDIES ON THE MECHANISM OF ETHANOL INDUCED HYPOGLYCEMIA

STUDIES ON THE MECHANISM OF ETHANOL INDUCED HYPOGLYCEMIA

Effect of ethanol on the conversion of fructose to glucose and glycogen by the isolated perfused liver* Glucose concentration in milligrams per 100 ml at minutes of perfusion.. Ethanol a[r]

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Genetic Determinants of Ethanol-Induced Liver Damage

Genetic Determinants of Ethanol-Induced Liver Damage

gations did not confirm this finding (13,14). This apparent discrepancy is likely to be due to the vari- able prevalence of this allele in the different popu- lations analyzed. Also in our work, association of the C2 allele with the development of ALD was ob- served only in Campogalliano, where the overall frequency of the allele in alcoholics was 0.11, while in Cormons, where the allelic frequency was 0.01—similar to the studies which failed to detect a positive association (13,14)—other genotypes pri- marily determined the risk of ALD. One of these genotypes is the homozygosity for allele ADH3*2 of ADH3. In individuals not possessing allele C2 of CYP2E1, the percentage of ADH3*2 homozygotes raised from 8% in healthy heavy drinkers, to 24% in ALD patients, and to 36% in ALD patients with cirrhosis. The ADH3*2 allele encodes for the 2 en- zymatic subunit of ADH3, which has lower ethanol oxidation activity. It can be speculated that, in the presence of this isoform, ethanol is primarily me- tabolized through the microsomal cytochrome P4502E1-mediated pathway, with a consequent higher production of toxic free radicals as end prod- ucts. In a previous study in the British population, Day and collaborators reported an association be- tween allele ADH3*1 (the rapid alcohol-metaboliz- ing allele) and ALD (18). This study, however, which was performed by comparing patients with alcoholic liver disease to normal individuals, showed only minor differences in allele distribu- tion between the two groups and was not confirmed by another independent investigation (11).
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Ethanol induced hyperlacticacidemia: inhibition of lactate utilization

Ethanol induced hyperlacticacidemia: inhibition of lactate utilization

The effects of oral ethanol administration on blood glucose and lactate concentrations, lactate inflow and outflow rates, and lactate incorporation into glucose were investigated in eight human volunteers. Lactate incorporation into glucose, lactate turnover, and lactate inflow and outflow rates were determined during an 8 hr constant infusion of 100 µCi of lactate-U- 14 C. Ethanol was administered by mouth at hourly intervals, 60 ml of bonded whiskey initially and 30 ml/hr thereafter. Blood lactate concentrations increased

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Ethanol-induced locomotor sensitization and ethanol consumption : the role of neuropeptide Y

Ethanol-induced locomotor sensitization and ethanol consumption : the role of neuropeptide Y

Interestingly, the fact that vapor exposed mice, regardless of viral treatment, exhibited increased anxiety-like behavior following withdrawal is consistent with other reports (Kotlinska & Bochenski, 2008; Overstreet et al., 2004). However, it is surprising that amygdalar infusion of rAAV-FIB-NPY did not reduce withdrawal- induced anxiety-like behavior in C57BL/6J mice. This is unexpected for several reasons. First, acute NPY is known to possess anxiolytic properties when infused centrally and into the amygdala (Heilig, 1993; Heilig, Soderpalm, Engel, & Widerlov, 1989). Second, rats show decreased NPY immunoreactivity in the amygdala 24 hours after withdrawal from chronic ethanol exposure (Roy & Pandey, 2002). Third, following chronic ethanol exposure, mutant mice lacking NPY display elevated anxiety-like responses (Sparta, Fee, Knapp, Breese, & Thiele, 2007). This discrepancy could be due to background strain effects as the NPY -/- mice mentioned above were maintained on a 129/SvEv while the current mice were C57BL/6J mice. Further, results from anxiety experiments may depend on the paradigm used to test anxiety-like behavior (Fee et al., 2004). Lastly, as with any chronic drug administration, we need to address the possibility that compensatory alterations in other NPY receptors masked the ability of NPY to be protect against withdrawal-induced anxiety.
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Journal of Applied Pharmaceutical Science

Journal of Applied Pharmaceutical Science

The aim of our study was to evaluate the gastro protective effect of aqueous extract of Juglans regia.L leaves in albino rats. Albino rats of wistar variety weighing 140-165gms were used in the experiment. The sexes were evenly divided into different treatment groups. The aqueous leaf extract of Juglans regia.L was investigated for its anti- ulcer activity against pylorus ligation, aspirin induced and ethanol induced gastric ulcer in rats at 500mg/kg body weight p.o. Histopathological assessment of rat stomach was carried out. A significant reduction (p<0.01) in ulcer index was seen in leaf extracts of Juglans regia.L treated rats of pylorus ligation, aspirin induced and ethanol induced gastric ulcer models. The gastro protective effect was further confirmed by histopathological examination of rat stomach. Thus the present study concludes the Juglans regia.L leaf extract having potential gastro protective effect in the three models tested.
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