Unveiling the interplay between NSAID-induced dysbiosis and autoimmune liver disease in children: insights into the hidden gateway to autism spectrum disorders. Evidence from ex vivo, in vivo, and clinical studies.

Autism spectrum disorders (ASD) represent a diverse group of neuropsychiatric conditions, and recent evidence has suggested a connection between ASD and microbial dysbiosis. Immune and gastrointestinal dysfunction are associated with dysbiosis, and there are indications that modulating the microbiota could improve ASD-related behaviors. Additionally, recent findings highlighted the significant impact of microbiota on the development of autoimmune liver diseases, and the occurrence of autoimmune liver disease in children with ASD is noteworthy. In the present study, we conducted both an in vivo study and a clinical study to explore the relationship between indomethacin-induced dysbiosis, autoimmune hepatitis (AIH), and the development of ASD. Our results revealed that indomethacin administration induced intestinal dysbiosis and bacterial translocation, confirmed by microbiological analysis showing positive bacterial translocation in blood cultures. Furthermore, indomethacin administration led to disturbed intestinal permeability, evidenced by the activation of the NLRP3 inflammasomes pathway and elevation of downstream biomarkers (TLR4, IL18, caspase 1). The histological analysis supported these findings, showing widened intestinal tight junctions, decreased mucosal thickness, inflammatory cell infiltrates, and collagen deposition. Additionally, the disturbance of intestinal permeability was associated with immune activation in liver tissue and the development of AIH, as indicated by altered liver function, elevated ASMA and ANA in serum, and histological markers of autoimmune hepatitis. These results indicate that NSAID-induced intestinal dysbiosis and AIH are robust triggers for ASD existence. These findings were further confirmed by conducting a clinical study that involved children with ASD, autoimmune hepatitis (AIH), and a history of NSAID intake. Children exposed to NSAIDs in early life and complicated by dysbiosis and AIH exhibited elevated serum levels of NLRP3, IL18, liver enzymes, ASMA, ANA, JAK1, and IL6. Further, the correlation analysis demonstrated a positive relationship between the measured parameters and the severity of ASD. Our findings suggest a potential link between NSAIDs, dysbiosis-induced AIH, and the development of ASD. The identified markers hold promise as indicators for early diagnosis and prognosis of ASD. This research highlights the importance of maintaining healthy gut microbiota and supports the necessity for further investigation into the role of dysbiosis and AIH in the etiology of ASD.

Hepatoprotective Role of Carvedilol against Ischemic Hepatitis Associated with Acute Heart Failure via Targeting miRNA-17 and Mitochondrial Dynamics-Related Proteins: An In Vivo and In Silico Study.

Acute heart failure (AHF) is one of the most common diseases in old age that can lead to mortality. Systemic hypoperfusion is associated with hepatic ischemia-reperfusion injury, which may be irreversible. Ischemic hepatitis due to AHF has been linked to the pathogenesis of liver damage. In the present study, we extensively investigated the role of mitochondrial dynamics-related proteins and their epigenetic regulation in ischemic liver injury following AHF and explored the possible hepatoprotective role of carvedilol. The biochemical analysis revealed that the ischemic liver injury following AHF significantly elevated the activity of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP) enzymes, the level of total and direct bilirubin, and the expression of hepatic mitogen-activated protein kinase (MAPK), dynamin-1-like protein (DNM1L), and hepatic miRNA-17. At the same time, it significantly reduced the serum albumin level, the activity of hepatic superoxide dismutase (SOD), and the expression of mitochondrial peroxisome proliferator-activated receptor-1α (PGC-1α), and mitofusin 2 (Mtf2). The histological examination of the liver tissue revealed degenerated hepatocytes. Interestingly, administration of carvedilol either prior to or after isoprenaline-induced AHF significantly improved the liver function and reversed the deterioration effect of AHF-induced ischemic hepatitis, as demonstrated by biochemical, immunohistochemical, and histological analysis. Our results indicated that the hepatoprotective effect of carvedilol in ameliorating hepatic ischemic damage could be attributed to its ability to target the mitochondrial dynamics-related proteins (Mtf2, DNM1L and PGC-1α), but also their epigenetic regulator miRNA-17. To further explore the mode of action of carvedilol, we have investigated, in silico, the ability of carvedilol to target dynamin-1-like protein and mitochondrial dynamics protein (MID51). Our results revealed that carvedilol has a high binding affinity (-14.83 kcal/mol) toward the binding pocket of DNM1L protein. In conclusion, our study highlights the hepatoprotective pharmacological application of carvedilol to attenuate ischemic hepatitis associated with AHF.

Acetylsalicylic Acid Suppresses Alcoholism-Induced Cognitive Impairment Associated with Atorvastatin Intake by Targeting Cerebral miRNA155 and NLRP3: In Vivo, and In Silico Study.

Alcoholism is one of the most common diseases that can lead to the development of several chronic diseases including steatosis, and cognitive dysfunction. Statins are lipid-lowering drugs that are commonly prescribed for patients with fatty liver diseases; however, the exact effect of statins on cognitive function is still not fully understood. In the present study, we have investigated the molecular and microscopic basis of cognitive impairment induced by alcohol and/or Atorvastatin (ATOR) administration to male Wistar albino rats and explored the possible protective effect of acetylsalicylic acid (ASA). The biochemical analysis indicated that either alcohol or ATOR or together in combination produced a significant increase in the nucleotide-binding domain-like receptor 3 (NLRP3), interleukin-1ß (IL-1ß) miRNA155 expression levels in the frontal cortex of the brain tissue. The histological and morphometric analysis showed signs of degeneration in the neurons and the glial cells with aggregations of inflammatory cells and a decrease in the mean thickness of the frontal cortex. Immunohistochemical analysis showed a significant increase in the caspase-8 immunoreaction in the neurons and glial cells of the frontal cortex. Interestingly, administration of ASA reversed the deleterious effect of the alcohol and ATOR intake and improved the cognitive function as indicated by biochemical and histological analysis. ASA significantly decreased the expression levels of miRNA155, NLRP3, and IL1B, and produced a significant decrease in caspase-8 immunoreaction in the neurons and glial cells of the frontal cortex with a reduction in the process of neuroinflammation and neuronal damage. To further investigate these findings, we have performed an extensive molecular docking study to investigate the binding affinity of ASA to the binding pockets of the NLRP3 protein. Our results indicated that ASA has high binding scores toward the active sites of the NLRP3 NACHT domain with the ability to bind to the NLRP3 pockets by a set of hydrophilic and hydrophobic interactions. Taken together, the present study highlights the protective pharmacological effect of ASA to attenuate the deleterious effect of alcohol intake and long term ATOR therapy on the cognitive function via targeting miRNA155 and NLRP3 proteins.

Cognitive effects of the GSK-3 inhibitor "lithium" in LPS/chronic mild stress rat model of depression: Hippocampal and cortical neuroinflammation and tauopathy.

Low-dose repeated lipopolysaccharide pre-challenge followed by chronic mild stress (LPS/CMS) protocol has been introduced as a rodent model of depression combining the roles of immune activation and chronic psychological stress. However, the impact of this paradigm on cognitive functioning has not been investigated hitherto. METHODS: This study evaluated LPS/CMS-induced cognitive effects and the role of glycogen synthase kinase-3ß (GSK-3ß) activation with subsequent neuroinflammation and pathological tau deposition in the pathogenesis of these effects using lithium (Li) as a tool for GSK-3 inhibition. RESULTS: LPS pre-challenge reduced CMS-induced neuroinflammation, depressive-like behavior and cognitive inflexibility. It also improved spatial learning but increased GSK-3ß expression and exaggerated hyperphosphorylated tau accumulation in hippocampus and prefrontal cortex. Li ameliorated CMS and LPS/CMS-induced depressive and cognitive deficits, reduced GSK-3ß over-expression and tau hyperphosphorylation, impeded neuroinflammation and enhanced neuronal survival. CONCLUSION: This study draws attention to LPS/CMS-triggered cognitive changes and highlights how prior low-dose immune challenge could develop an adaptive capacity to buffer inflammatory damage and maintain the cognitive abilities necessary to withstand threats. This work also underscores the favorable effect of Li (as a GSK-3ß inhibitor) in impeding exaggerated tauopathy and neuroinflammation, rescuing neuronal survival and preserving cognitive functions. Yet, further in-depth studies utilizing different low-dose LPS challenge schedules are needed to elucidate the complex interactions between immune activation and chronic stress exposure.

N-acetylcysteine (NAC) alleviates the peripheral neuropathy associated with liver cirrhosis via modulation of neural MEG3/PAR2/ NF-Ò¡B axis.

BACKGROUND AND AIM: Oxidative stress (OS) is accused in pathogenesis of many diseases, including liver cirrhosis by many mechanisms. One of them is the disturbance of long non coding maternally expressed 3 (MEG3)/protease activated receptor 2 (PAR2) downstream pathway. We aimed to investigate the role of this axis in cirrhotic neuropathy and whether an antioxidant compound such as N-acetylcysteine (NAC) could improve the peripheral nerve function through repression of MEG3/PAR2. METHODS: Thirty Wistar rats were used and divided into 5 groups; naive, thiacetamide (TAA) (200 mg/kg 3 times/week. i.p. for 8 weeks) and TAA+NAC (50 or 100 or 200 mg/kg/day) groups. Von Frey (VF) test for mechanical nociceptive responses, hepatic& neural MEG3, NF-Ò¡B and neural PAR2 expression by PCR, histological studies for liver and sciatic nerve together with the dorsopedal skin thickness were done. RESULTS: TAA induced significant decrease in liver function, negative VF test, an increase in the expression of hepatic& neural MEG3, NF-Ò¡B and neural PAR2. The histological studies showed cirrhotic changes with atrophy of the sciatic nerve and the dorsal skin. NAC improved the liver function together with reversal of the neural: functional, biochemical and histological changes in a dose dependent manner. CONCLUSIONS: NAC could improve the peripheral neuropathy in cirrhotic rat through suppression of MEG3/PAR2 expression.

Modulation of hippocampal TLR4/BDNF signal pathway using probiotics is a step closer towards treating cognitive impairment in NASH model.

BACKGROUND AND AIM: Disturbance of gut microbiota plays a role in induction and progression of non alcoholic steatohepatitis (NASH) and the associated cognitive dysfunction. We supposed that high fat diet (HFD)-induced dysbiosis may lead to NASH/cognitive impairment co-morbidities through hippocampal TLR4/BDNF signaling pathway and the regaining of microbiota balance through probiotics could provide a therapeutic option. METHODOLOGY: Four groups of male Wister rats were used; Naïve, Lactobacillus Plantarum EMCC-1039 (LP EMCC-1039), NASH and NASH+ LP EMCC-1039 groups. After induction of NASH with high fat diet (HFD), LP EMCC-1039 was given daily by oral gavage in the last two weeks of experiment to the treated group. Body weight percentage (BW%) changes, Lee index (LI), liver function tests, expression of BDNF, TLR4 with RT-PCR and quantification of BDNF, TLR4 by ELISA were measured . Histological studies and assessment of cognitive function were also performed. RESULTS: NASH group showed an increase in BW% and LI . It was associated with cognitive deficits, an increase in hepatic, hippocampal TLR4 expression and decline in BDNF expression and protein, all p values were <0.05. Histological examination revealed significant decrease in number of viable cells and shrinking of pyramidal cells in hippocampus (p<0.05). Treatment with LP EMCC-1039 improved all these pathological changes significantly (p<0.05) with negative correlation between NAFLD activity score (NAS) and cognitive measurements. Additionally, hepatic and hippocampal TLR4 expression were decreased and BDNF expression and quantity were increased. CONCLUSIONS: Dysbiosis-induced NASH was associated with cognitive impairment and a probiotic (LP EMCC-1039) supplementation has beneficial effect through modulation of TLR4/BDNF signaling pathway.

Involvement of TLR4/ CXCL9/ PREX-2 pathway in the development of hepatocellular carcinoma (HCC) and the promising role of early administration of lactobacillus plantarum in Wistar rats.

BACKGROUND AND AIM: Improvement of gut microbiota may help in preventing the progression of cirrhosis. We supposed that Lactobacillus Plantarum (L. Plantarum) protects the cirrhotic liver through suppression of TLR4/ CXCL9/ PREX-2. METHODOLOGY: Rats were divided into two groups. Group I, lasts for six weeks and Group II lasts for 12 weeks. Each group was subdivided into: naïve, Lactobacillus Plantarum (L. Plantarum), thioacetamide (TAA) and TAA + L. Plantarum. Liver function tests, α fetoprotein (AFP) levels, CXCL9, PREX-2 and TLR4 expression were assessed. Histological studies were performed. RESULTS: TAA induced significant deterioration in liver functions and increased AFP. There was periportal cirrhosis, vacuolated hepatocytes, decrease hepatocyte parrafin-1 (hep par-1) expression, increase proliferating cell nuclear antigen (PCNA) positive nuclei and cytokeratin AE1/AE3. The PCR results showed significant increase in TLR4, CXCL9 and PREX-2 expression. Early administration of L. Plantarum significantly decreased the expression of TLR4, CXCL9 and PREX-2 together with improvement in liver function and prevented the pathological changes. CONCLUSIONS: The cirrhotic complications induced by TAA are through activation of TLR4/ CXCL9/ PREX-2 pathway and could be prevented by the early administration of L. Plantarum.

Exenatide promotes cardiac lncRNAs HOX transcript antisense RNA (HOTAIR) in Wistar rats with liver cirrhosis; a novel role of GLP-1 receptor agonists in cirrhotic cardiomyopathy.

Long acting non-coding RNAs lncRNAs HOX Transcript Antisense RNA (HOTAIR) is cardioprotective and mediates its effect through sirtulin 1 (SIRT1). The decrease in HOTAIR expression predisposes to various types of cardiomyopathy. We aimed to investigate whether decrease HOTAIR expression is involved in cirrhotic cardiomyopathy or not and the role of glucagon like peptide 1 receptor (GLP-1 receptor) in facilitating its effect through studying the effect of a exenatide (EXA), on cardiac function as well as the expression of some relevant bio-molecules. Rats were used and divided into: naïve, EXA, Thioacetamide (TAA) and TAA + EXA groups. ECG, dobutamine stress test (DST) were done. AST, ALT, fasting blood glucose, troponin I were measured. Cardiac HOTAIR & SIRT1, hepatic and cardiac GLP-1 receptor expression levels were investigated in addition to histological studies. Our results showed that EXA administration in control rats produced no significant changes. TAA induced cirrhosis with insulin resistance and significant changes in cardiac functions. GLP-1 receptor, HOTAIR and SIRT1 expression in cardiac tissue were significantly decreased with a significant increase in troponin I. EXA + TAA group showed a restoration of the hepatic architecture and function. EXA treatment produced significant improvement in cardiac parameters and was associated with increasing the expression of cardiac GLP-1 receptor, HOTAIR. The cardiac muscle showed an apparent decrease in collagen fibers. So we can conclude that EXA promotes the protective effect of HOTAIR on cardiac structure and function in rat model of cirrhosis which may introduce a new therapeutic strategy in cirrhotic cardiomyopathy.

Targeting HMGB1/TLR4 axis and miR-21 by rosuvastatin: role in alleviating cholestatic liver injury in a rat model of bile duct ligation.

Many pathways are involved in the association between biliary obstruction and liver injury. We investigated the intervention influence and effect of rosuvastatin (Rvs) on the high mobility group protein 1 (HMGB1)/toll-like receptor-4 (TLR4) axis and microRNA-21 (miR-21) in cholestatic liver injury. This model was performed by ligating common bile duct of Wistar rats. Saline and Rvs were orally administrated by gastric gavages. Liver and blood samples were collected and subjected to molecular and biochemical evaluation. We found that the daily oral administration of Rvs was protective against the occurrence of cholestatic liver injury. This was evident from the results of hepatic, oxidative stress, and inflammatory biomarkers. This study also revealed the Rvs inhibitory effect on the HMGB1/TLR4 intracellular signaling axis as evidenced by decreasing the levels of nuclear factor κß (NFκß), tumor necrosis factor α (TNFα), and interleukin 6 (IL6) production. Furthermore, Rvs-treated group showed a significant reduction in the expression of miR-21 in comparison to the untreated group. Accordingly, rosuvastatin interference with the HMGB1/TLR4 and miR-21 expression could explain its hepatoprotective effect in cholestatic liver injury.

Insights into hepatic and renal FXR/DDAH-1/eNOS pathway and its role in the potential benefit of rosuvastatin and silymarin in hepatic nephropathy.

OBJECTIVES: The repression of renal Farnesoid X Receptor (FXR) had been shown to result from lack of bile acid production from cirrhotic liver. We hypothesized that silymarin and rosuvastatin (Rvs) could have a hepatorenal therapeutic effects in hepatic nephropathy through induction of FXR. METHODS: Forty two male Wistar rats were used; naïve (n = 12); six of them were sacrificed after 4 weeks and six continued till the end of the experiment. Thirty rats were treated as follows: Rvs, silymarin, thioacetamide (TAA), TAA + Rvs and TAA + silymarin. Liver and kidney function tests as well as the renal and hepatic expression of transforming growth factor ß1 (TGFß1), FXR, dimethylarginine dimethylaminohydrolase-1 (DDAH-1) and eNOS were performed. Histological and immuno-histochemical studies of liver and kidney were also done. RESULTS: TAA-inducted liver cirrhosis was associated with significant deterioration of liver and renal functions together with increasing expression of hepatic and renal TGFß1 and decreasing expression of hepatic and renal FXR, DDAH-1 and eNOS. Giving silymarin or Rvs induced hepatic and renal improvement which was evidenced biochemically and histologically. Significant positive correlation was detected between all the investigated biomarkers except for the correlation between FXR and TGFß1 which was negative. CONCLUSIONS: In conclusion, liver cirrhosis is associated with deterioration of renal functions. Silymarin and Rvs have a potential hepatorenal therapeutic benefit through simultaneous enhancement of FXR/DDAH-1/eNOS pathway in both organs.

Targeting NLRP3 inflammasome via acetylsalicylic acid: Role in suppressing hepatic dysfunction and insulin resistance induced by atorvastatin in naïve versus alcoholic liver in rats.

BACKGROUND: NLRP3 inflammasome is described in many pathological conditions and is also involved in drug induced liver injury. AIM OF THE WORK: To investigate the role of NLRP3 inflammasome in liver injury induced by chronic alcohol and/or atorvastatin ingestion. MATERIALS AND METHODS: Sixty male Wistar rats were used. They were divided into 5 groups: (I) control naïve (II) Alcoholic: given ethanol 8 g/kg/day, p.o (III) Atorvastatin: given atorvastatin 10 mg/kg/day, p.o. (IV) Alcoholic + atorvastatin (V) Acetylsalicylic acid (ASA): given ASA 10 mg/kg/day, p.o together with alcohol and atorvastatin. Isolated perfused liver, biochemical and histological studies were done. RESULTS: Atorvastatin and alcohol induced liver inflammation with increasing the expression of NLRP3, IL-1ß and caspase-8 immune-reaction. Atorvastatin and alcohol decreased the reduced form of glutathione in hepatic tissues and induced insulin resistance. ASA administration alleviated the hepatotoxic effects of alcohol and atorvastatin to a significant extent. CONCLUSIONS: Acetylsalicylic acid alleviated the hepatotoxic effects of alcohol and atorvastatin through decreasing the production of NLRP3 inflammasome in rats' liver.

The protective effect of pentoxifylline versus silymarin on the pancreas through increasing adenosine by CD39 in a rat model of liver cirrhosis: Pharmacological, biochemical and histological study.

Impaired glucose homoeostasis due to insulin resistance and decrease sensitivity of pancreatic ß-cells is a feature of liver disease and results into hepatogenous diabetes. Decrease expression of CD39 was linked to inflammation and occurrence of diabetes. Therefore, we performed this study to explore the protective effect of pentoxifylline (PTX) and silymarin administration on the ß-cells of the pancreas in a rat model of thioacetamide induced liver cirrhosis. Biochemical, histological and immunohistochemistry studies of the liver and pancreas were performed and provided an evidence on the protective effect of PTX to pancreatic ß-cells compared to silymarin. Also, silymarin induced a significant improvement of liver cirrhosis compared to PTX. In conclusion, the potential protective effect of PTX against ß-cells deterioration could be attributed to increasing pancreatic CD39 expression and the subsequent increase of adenosine.

Metformin potentiates cognitive and antidepressant effects of fluoxetine in rats exposed to chronic restraint stress and high fat diet: potential involvement of hippocampal c-Jun repression.

Several hypotheses link high fat diet (HFD) with the pathophysiology of depression and its response to antidepressants. This study aimed to determine the effect of metformin (MET) on the cognitive and antidepressant activity of fluoxetine (FLU) through its effect on c-Jun expression. Behavioral, cognitive function, biochemical, and histopathological studies were performed in non-HFD- and HFD-fed rats exposed to chronic restraint stress (CRS). Stressed group showed cognitive impairment, depressive-like symptoms, disturbed glucose homeostasis and lipid profile, reduced adiponectin level, brain-derived neurotrophic factor (BDNF) expression, and increased corticosterone and c-Jun. All these were aggravated by HFD. MET, FLU and their combination produced significant improvement in lipid profile with significant increase in adiponectin and BDNF expression. Corticosterone, body weight and insulin resistance showed significant decrease in the treated groups. Moreover, there was a significant decrease in hippocampal c Jun expression. There was a significant preferable effect toward the combination. Conclusion, MET may decrease the refractoriness to FLU and improves the cognition in individuals who are fed on HFD.

Potential involvement of PPAR α activation in diminishing the hepatoprotective effect of fenofibrate in NAFLD: Accuracy of non- invasive panel in determining the stage of liver fibrosis in rats.

BACKGROUND: Although Fenofibrate (FF) is a hypolipedmic drug and one of the PPARα agonists which is a drug target for non alcoholic liver disease (NAFLD), no studies had investigated its potential hepatic effects in such cases. AIM: To compare between the effect of FF and Gemfibrozil (GF) on the prognosis of NAFLD in rats. METHODS: Sixty four rats were used and classified into two main groups. Group I (treated for 6 weeks): naïve, FF, GF groups and Group II (treated for 14 weeks and drugs were added at the last 6 weeks): Control, high fat diet (HFD) untreated, HFD+FF, HFD+FF+folic acid (FA) and HFD+GF groups. Body weight (BW), liver index (LI), renal perfusion test (RPT), glomerular filtration rate (GFR), serum creatinine (S.cr), plasma homocysteine (Hcy), liver function, non invasive markers of fibrosis and histopathology were done. RESULTS: HFD produced significant increase (P<0.05) in BW, LI, S.cr, plasma Hcy, lipid profile and liver enzymes. It showed significant (P<0.05) decrease in GFR and RPT. These findings were correlated to the histopathology. FF through its effect on GFR and renal function induced significant increase in plasma Hcy and that decreased its effectiveness in managing NAFLD associated with hyperlipidemia. The addition of FA improved significantly its hypolipidemic and hepatotoxic effects.GF showed none of the above FF effects and this may be due to its low affinity to PPAR α. CONCLUSIONS: There is preference of adding FA to FF or using GF instead in cases of NAFLD. Moreover, this work implies the enhanced liver fibrosis (ELF) panel diagnostic performance in diagnosis of any and moderate degree of fibrosis in rats with NAFLD.

Potential involvement of JNK1 repression in the hepatic effect of sitagliptin and metformin in rats subjected to high fat diet and chronic mild distress.

BACKGROUND: Depression and non-alcoholic steatohepatitis (NASH) are highly co-morbid, and hepatic JNK pathway may be involved in their relation. AIM: To evaluate the impact of depression on NASH through the involvement of JNK1 and to assess the effect of sitagliptin and metformin on hepatic JNK1 expression in both NASH and NASH associated with depression. METHODS: Eight groups of male Wistar rats were used: naïve rats, non-stressed NASH, non-stressed NASH sitagliptin treated, non-stressed NASH metformin treated, stressed, stressed NASH untreated, stressed NASH sitagliptin treated and stressed NASH metformin treated. Behavioral, biochemical, molecular and histopathological studies were performed. RESULTS: Non-stressed NASH group showed depressive like symptoms, disturbed glucose homeostasis, impairment of liver functions, decrease adiponectin and increase malondialdehyde, which were aggreviated by stress. Sitagliptin produced significant improvement compared to metformin regarding biochemical and histopathological parameters. Furthermore, sitagliptin significantly decreased expression of hepatic JNK1 in both stressed and non-stressed rats. All these changes were accompanied by significant improvement of behavioral changes. CONCLUSIONS: The link between NASH and depression raised the role of JNK activation through increase expression of JNK1. Since sitagliptin was associated with preferable effects than metformin, therefore, it is potentially preferred in the management of either NASH or NASH associated with depression.

Fenofibrate A peroxisome proliferator activated receptor-α agonist treatment ameliorates Concanavalin A-induced hepatitis in rats.

Peroxisome proliferator-activated receptor-α (PPARα) is physiologically highly expressed by hepatocytes, where it plays a pivotal anti-inflammatory and metabolic role. The decrease expression and functional activity of PPARα in hepatocytes during hepatitis C virus infection may contribute to the pathogenesis of the disease in humans. This study aims at evaluating the effects of PPARα activation with fenofibrate (FF) on liver inflammation, fibrosis and portal pressure (PP) in Concanavalin A (Con A)- induced hepatitis in rats. The rats were randomly divided to 3 groups; control (1 ml saline iv/wk) group, Con A (20mg/kg/iv/wk) group and Con A with FF (100mg/kg/day p.o) group. Blood samples and livers were collected by the end of the first, second, fourth and eighth injections of Con A for biochemical, histopathological and immunohistochemistry studies for α-smooth muscle actin (α SMA). Measurement of PP was performed by the end of the 8th week. FF group had a significant (P<0.05) decrease of serum alanine and aspartate aminotransferases with significant reduction of hepatic tumor necrosis factor alpha and malondialdehyde levels than Con A group. Histopathological examination revealed that treatment with FF significantly suppressed early inflammation, reduced α SMA, and apoptosis of hepatocytes induced by Con A, thereby preventing the progression of chronic liver injury and fibrosis. In addition FF group had a significantly lower PP (-89.0%) than Con A group. In conclusion PPARα activation significantly reduced liver inflammation, fibrosis and PP in Con A model of hepatitis that may represent a new therapeutic strategy for hepatitis and its complications.