Oleuropein Reverses Repeated Corticosterone-Induced Depressive-Like Behavior in mice: Evidence of Modulating Effect on Biogenic Amines.

Depression is still one of challenging, and widely encountered disorders with complex etiology. The role of healthy diet and olive oil in ameliorating depression has been claimed. This study was designed to explore the effects of oleuropein; the main constituent of olive oil; on depression-like behaviors that are induced by repeated administration of corticosterone (40 mg/kg, i.p.), once a day for 21 days, in mice. Oleuropein (8, 16, and 32 mg/kg, i.p.) or fluoxetine (20 mg/kg, positive control, i.p.1) was administered 30 minutes prior to corticosterone injection. Sucrose consumption test, open-field test (OFT), tail suspension test (TST), and forced swimming test (FST) were performed. Reduced Glutathione (GSH), lipid peroxidation, and biogenic amines; serotonin, dopamine, and nor-epinephrine; levels were also analyzed in brain homogenates. Corticosterone treatment induced depression-like behaviors, it increased immobility time in the TST, OFT, and FST, decreased the number of movements in OFT, and decreased sucrose consumption. Corticosterone effect was associated with depletion of reduced glutathione and increase of lipid peroxidation, in addition to modification of biogenic amines; decreased serotonin and dopamine. Oleuropein or fluoxetine administration counteracted corticosterone-induced changes. In conclusion, oleuropein showed a promising antidepressant activity, that is evident by improving corticosterone-induced depression-like behaviors, and normalizing levels of biogenic amines.

Carnosine and L-arginine attenuate the downregulation of brain monoamines and gamma aminobutyric acid; reverse apoptosis and upregulate the expression of angiogenic factors in a model of hemic hypoxia in rats.

PURPOSE: The purpose of the present study was to investigate the preventive effect of L-arginine (ARG) and carnosine (CAR) on hypoxia-induced neurotoxicity in rats. The impact on neuro-inflammation, apoptosis, angiogenesis, and the brain levels of monoamines and GABA were investigated. METHODS: Rats were divided into the following: normal control, hypoxia model induced by sodium nitrite (75 mg/kg s.c), and hypoxic rats pre-treated with CAR (250 mg/kg), ARG (200 mg/kg), and their combination. RESULTS: Data revealed that hypoxia induced significant elevation of hypoxia inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), and its receptor reflecting the stimulation of angiogenesis. Hypoxia also resulted in increased inflammatory mediators-including nuclear factor kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). In addition, hypoxia initiates cerebral apoptosis as revealed by increased caspase-3 and BAX with reduced Bcl-2. These changes were associated with reduced brain levels of GABA and monoamines including noradrenaline (NADR), dopamine (DOP), and serotonin (SER). Pre-treatment with ARG and/or CAR significantly mitigated the neural changes induced by hypoxia and attenuated the elevated levels of NF-κB, TNF-α, IL-6, caspase-3, and BAX, while ameliorated the reduced levels of Bcl-2, NADR, DOP, SER, and GABA, with the best improvement observed with the combination. Further elevation of the angiogenic markers was observed indicating their role in boosting oxygen delivery to brain. CONCLUSION: CAR, ARG, and, importantly, their combination could effectively protect against hypoxia-induced neurotoxicity, via their angiogenic, anti-inflammatory, and anti-apoptotic properties in addition to reversing the effect on GABA and monoamines.

Physicochemical and pharmacodynamic evaluation of pioglitazone binary systems with hydrophilic carriers.

Pioglitazone (PGZ) is an antidiabetic agent belongs to thiazolidinediones. Binary systems of PGZ in the matrices of kollicoat IR (KL) and gelucire (GL) at different weight ratios were prepared by kneading and co-evaporation methods, respectively. The drug solid dispersions were characterized in terms of in vitro dissolution studies, differential scanning calorimetry (DSC), and X-ray powder diffraction (XRPD). The effects of PGZ-KL (1:4) solid dispersion on the body weight, blood glucose, renal and hepatic functions of the diabetic rats were evaluated. Enhanced drug dissolution was observed in the case of PGZ-KL binary systems depending on the drug to polymer weight ratio. A reduction of 39.7, 32.7 and 26.6% for diabetic control, PGZ untreated and PGZ-KL (1:4), respectively, was recorded after 2 weeks. PGZ-KL (1:4) solid dispersion also showed significantly lower glucose blood level (p < 0.05) compared to the diabetic control group along the period of experiment. The level of ALT was highly significantly decreased in the animal group treated with PGZ-KL solid dispersion (p < 0.001). However, treatment of diabetic rats with either PGZ-KL or PGZ untreated significantly reduced the level of creatinine compared to the diabetic control and the difference between them was non-significant.

Roles of some antioxidants in modulation of cardiac myopathy induced by sodium nitrite via down-regulation of mRNA expression of NF-κB, Bax, and flt-1 and suppressing DNA damage.

The underlying pathology of cardiac damage involves various molecular and signaling pathways. Therefore, this study aimed to explore the role of Quercetin (Querc), alone or in combination with Melatonin (Melat) against cardiac damage induced by sodium nitrite (Sod nit), as well as to elucidate different signaling pathways. Querc and Melat were injected intraperitoneally (i.p.), followed by induction of hypoxia in rats by using a single dose of Sod nit (60 mg/kg, s.c.). Treatment with Sod nit significantly decreased hemoglobin (Hb) levels in blood. Pretreatment of hypoxic rats with Querc and/or Melat elevated the declined Hb concentration. The forementioned antioxidants also successfully ameliorated the alteration of heat shock protein 70 (HSP-70) and markers of cardiac injury, including troponin T (Trop. T), creatine kinase-MB (CK-MB), tumor necrosis factor-α (TNF α), and C-reactive protein (CRP) in the rats serum. Furthermore, RT-PCR revealed that these antioxidants successfully modulated mRNA expression of NF-κB, Bax, Bcl-2, and flt-1. They also regulated vascular endothelial growth factor (VEGF), the apoptosis marker caspase 3, and oxidative DNA damage in cardiac tissue, compared to Sod nit-intoxicated rats. The present biochemical results are reinforced by histopathological examination. IN CONCLUSION: The results reflected that treatment with Querc in combination with Melat was most effective in improving Sod nit-toxicity induced cardiac damage, thus confirming the promising role of this combination as an effective treatment for cardiac damage induced by other cardio-toxic agents.

Sitagliptin attenuates myocardial apoptosis via activating LKB-1/AMPK/Akt pathway and suppressing the activity of GSK-3ß and p38α/MAPK in a rat model of diabetic cardiomyopathy.

The present study aimed to investigate the protective effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on diabetic cardiomyopathy (DCM)-associated apoptosis and if this effect is mediated via modulating the activity of the survival kinases; AMP-activated protein kinase (AMPK) and Akt & the apoptotic kinases; glycogen synthase kinase-3 ß (GSK-3ß) and p38 mitogen-activated protein kinase (p38MAPK). Diabetes was induced by a single intraperitoneal injection of streptozotocin (55 mg/kg). Diabetic rats were treated with sitagliptin (10 mg/kg/day, p.o.) and metformin (200 mg/kg/day, p.o. as positive control) for six weeks. Chronic hyperglycemia resulted in elevation of serum cardiac biomarkers reflecting cardiac damage which was supported by H&E stain. The mRNA levels of collagen types I and III were augmented reflecting cardiac fibrosis and hypertrophy which was supported by Masson trichome stain and enhanced phosphorylation of p38MAPK. Cardiac protein levels of cleaved casapse-3, BAX were elevated, whereas, the levels of Bcl-2 and p-BAD were reduced indicating cardiac apoptosis which could be attributed to the diabetes-induced reduced phosphorylation of Akt and AMPK with concomitant augmented activation of GSK-3ß and p38MAPK. Protein levels of liver kinase B-1, the upstream kinase of AMPK were also supressed. Sitagliptin administration alleviated the decreased phosphorylation of AMPK and Akt, inactivated the GSK-3ß and p38 AMPK, therefore, attenuating the apoptosis and hypertrophy induced by hyperglycemia in the diabetic heart. In conclusion, sitagliptin exhibits valuable therapeutic potential in the management of DCM by attenuating apoptosis. The underlying mechanism may involve the modulating activity of AMPK, Akt, GSK-3ß and p38MAPK.

Downregulation of flt-1 and HIF-1α Gene Expression by Some Antioxidants in Rats Under Sodium Nitrite-Induced Hypoxic Stress.

This study assessed the effect of L-arginine (L-argin), carnosine (carno), or their combination in the amelioration of certain biochemical indices induced in the liver of hypoxic rats. Hypoxia was induced via sodium nitrite (S.nit) injection at a dose of 75 mg/kg. Rats were administered L-argin (250 mg/kg) or carno (250 mg/kg), either alone or in combination, 24 hours and 1 hour prior to S.nit intoxication. Hypoxia significantly elevated serum alanine aminotransferase, in addition to a significant upregulation of hepatic heat shock protein 70 with concurrent reduction in the level of vascular endothelial growth factor. Moreover, hepatic vascular endothelial growth factor 1 (flt-1), hypoxia inducible factor-1α gene expression, and cytochrome P450 levels were elevated, compared with the normoxic group. The antioxidants, administered either alone or in combination, markedly downregulated all of the previously mentioned biomarkers, compared to the hypoxic rats. Histopathological examination revealed hepatocellular degeneration and nuclear pyknosis, in addition to inflammatory cellular infiltration in the hypoxic rats, whereas treatment with the studied antioxidants improved the liver architecture. The present data revealed the efficacy of L-argin and carno in ameliorating the hepatic damage induced via angiogenic markers in response to hypoxia, the combination regimen showing the superior effect.

Simvastatin ameliorates diabetic nephropathy by attenuating oxidative stress and apoptosis in a rat model of streptozotocin-induced type 1 diabetes.

Statins are HMG-CoA reductase inhibitors with lipid-lowering effect and commonly used to reduce cardiovascular risk in diabetic patients. The present study investigates the ameliorative effect of simvastatin (SIM) on diabetic nephropathy in rats, pointing to its anti-apoptotic and anti-oxidative stress efficacies. Diabetes was induced by a single intraperitoneal injection of 55 mg/kg body weight streptozotocin (STZ) and both control and diabetic rats received 10 mg/kg SIM for 90 days. Treatment with SIM diminished the body weight loss, blood glucose and, serum creatinine, urea and uric acid in diabetic rats. SIM improved the creatinine clearance rate and urinary levels of creatinine, urea and albumin in STZ-induced rats. Lipid peroxidation and nitric oxide (NO) were significantly increased in the diabetic kidney whereas reduced glutathione, SOD and catalase were declined. Bax and caspase-3 showed a significant increase and Bcl-2 was decreased in the kidney of diabetic rats. SIM administration reduced lipid peroxidation and NO, and improved antioxidants and the expression of apoptotic markers. Diabetic rats showed increased collagen deposition in the kidney, atrophied irregular renal corpuscles with collapsed glomeruli and tubules with degenerated epithelial lining, an effect that was reversed following treatment with SIM. In conclusion, SIM can protect against diabetic nephropathy by attenuating oxidative stress and apoptosis.

Possible protective mechanisms exerted by metformin or metformin and vitamin E in isoproterenol-induced cardiac injury.

Several studies have reported that metformin is cardioprotective for diabetic and non-diabetic ischemic hearts through mechanisms that cannot be entirely attributed to its anti-hyperglycemic effect. This study was designed to investigate the cardioprotective effects of metformin with and without vitamin E after induction myocardial infarction (MI) in rats, using isoproterenol. Administration of metformin or vitamin E significantly reduced the cardiac mass index (P < 0.01), ameliorated the changes to cardiac biomarkers, and attenuated oxidative stress levels compared to the isoproterenol group. Interestingly, combination therapy showed a slight synergistic effect. Histopathological analysis suggested that metformin treatment reduced NF-κB expression and protected against isoproterenol-induced MI. Our results indicate that metformin mediates a cardioprotective effect against isoproterenol-induced MI via antioxidant activity and modulation of the NF-κB signaling pathway. This suggests that metformin would be beneficial in MI treatment.

Simvastatin Ameliorates Diabetic Cardiomyopathy by Attenuating Oxidative Stress and Inflammation in Rats.

Simvastatin is a lipid-lowering agent used to treat hypercholesterolemia and to reduce the risk of heart disease. This study scrutinized the beneficial effects of simvastatin on experimental diabetic cardiomyopathy (DCM), pointing to the role of hyperglycemia-induced oxidative stress and inflammation. Diabetes was induced by intraperitoneal injection of streptozotocin and both control and diabetic rats received simvastatin for 90 days. Diabetic rats showed significant cardiac hypertrophy, body weight loss, hyperglycemia, and hyperlipidemia. Serum creatine kinase MB (CK-MB) and troponin I showed a significant increase in diabetic rats. Simvastatin significantly improved body weight, attenuated hyperglycemia and hyperlipidemia, and ameliorated CK-MB and troponin I. Simvastatin prevented histological alterations and deposition of collagen in the heart of diabetic animals. Lipid peroxidation and nitric oxide were increased in the heart of diabetic rats whereas antioxidant defenses were decreased. These alterations were significantly reversed by simvastatin. In addition, simvastatin decreased serum inflammatory mediators and expression of NF-κB in the diabetic heart. Cardiac caspase-3 was increased in the diabetic heart and decreased following treatment with simvastatin. In conclusion, our results suggest that simvastatin alleviates DCM by attenuating hyperglycemia/hyperlipidemia-induced oxidative stress, inflammation, and apoptosis.

Amelioration of panadol-induced nephrotoxicity via down-regulation of Bax/Bcl2 ratio with some antioxidants.

BACKGROUND: Overdoses of Panadol (APAP) result in hepatic and renal toxicity. Up till now, there is no effective drug for APAP-enhanced nephrotoxicity. This work aims to explore the protective effects of N-acetylcysteine, Thymoquinone (THQ), Curcumin (CUR) and α-Lipoic acid (LA) either alone or in combination against APAP nephrotoxicity, focused on modulation of Bax/Bcl2 pathway. METHODS: APAP was administrated at a single dose then treated with the fore mentioned antioxidants. RESULTS: APAP administration increased serum creatinine, urea, uric acid, tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß) levels compared to control group. There is a marked depletion of reduced glutathione (GSH) levels and superoxide dismutase activity (SOD), Bax level was overexpressed, whereas Bcl2 was downregulated in renal tissue. Histopathological examination of the kidney tissue supported these biochemical findings. Treatment with the fore mentioned anti-oxidants ameliorated most of the previous evaluated parameters and returned the kidney nearly to its normal architecture. CONCLUSION: The expression of Bax and Bcl2 is considered one of the mechanisms underlying APAP-induced nephrotoxicity. The administration of THQ along with CUR could be a promising antidote for APAP renal damage through their antioxidant potential.

Attenuation of DNA damage and mRNA gene expression in hypoxic rats using natural antioxidants.

This study aimed to explore the efficiency of carnosine (Cs) and/or l-arginine (Agn) in the downregulation of apoptotic and inflammatory molecule expression and DNA damage caused hepatic injury in response to sodium nitrite (Sd)-induced hypoxia in rats. Rats were injected with Sd; Agn or/and Cs were administrated prior to Sd intoxication. Sd significantly decreased hemoglobin concentration and Bcl-2 mRNA expression, while increased expressions of apoptotic markers (Bax and caspase), tumor necrosis factor-α, nuclear factor kappa B, and C-reactive protein and the oxidative DNA damage in hepatic tissue. Moreover, administration of Agn or/and Cs exhibited a modulation of the previous parameters. However, concurrent treatment with the forementioned antioxidants modulated these levels. It was concluded that the treatment with the combination of Agn and Cs was the most effective regimen in ameliorating Sd toxicity accompanied by hypoxic stress.

Original research paper. Pulmonary prophylactic impact of melatonin and/or quercetin: A novel therapy for inflammatory hypoxic stress in rats.

The study aims to compare, through histological and biochemical studies, the effects of quercetin, melatonin and their combination in regulation of immuno-inflammatory mediators and heat shock protein expressions in sodium nitrite induced hypoxia in rat lungs. The results revealed that NaNO2 injection caused a significant decrease in Hb in rats, while serum levels of TNF-α, IL-6 and CRP, VEGF and HSP70 were elevated compared to the control group. Administration of melatonin, quercetin or their combination before NaNO2 injection markedly reduced these parameters. Histopathological examination of the lung tissue supported these biochemical findings. The study suggests that melatonin and/or quercetin are responsible for lung tissue protection in hypoxia by downregulation of immuno-inflammatory mediators and heat shock protein expressions. Pre-treatment of hypoxic animals with a combination of melatonin and quercetin was effective in modulating most of the studied parameters to near-normal levels.

Role of Different Natural Antioxidants in the Modulation of mRNA-expression of Apoptotic Molecules in the Livers of Carbon Tetrachloride-Intoxicated Rats.

Overexpression of nuclear factor (NF-κB) or activation of Smad3 by transforming growth factor ß (TGF-ß1) induced by oncogenes results in overexpression of fibrotic processes and hence cell death. The objective of this study is to examine whether Silymarin (Sil) alone or in combination with Vitamin E (Vit E) and/or Curcumin (Cur) plays a modulatory role against the overexpression of NF-κB, and TGF-ß that induced in response to carbon tetrachloride (CCl4) administration. The present work revealed that CCl4 induced elevation of in serum alanine aminotransferase (ALT), Apoptosis regulator (Bax), Smad3, TGF-ß, and NF-kB hepatic mRNA expression (using Real-time PCR), administration of Sil alone downregulated these expressions. Treatment with Vit E acid and/ or Cur along with Sil produced best results in this concern. B-cell lymphoma 2 (Bcl-2) expressions were downregulated by CCl4; whereas concurrent treatment of Vit E and/or Cur along with Sil increased its expression. On conclusion, the use of Vit E and/or Cur could potentiate the antiapoptotic action of Sil.

Quercetin inhibits sodium nitrite-induced inflammation and apoptosis in different rats organs by suppressing Bax, HIF1-α, TGF-ß, Smad-2, and AKT pathways.

The objective of this work is to study the protective effects of Quercetin against sodium nitrite-induced hypoxia on liver, lung, kidney and cardiac tissues, also to explore novel mechanism of this compound. Male albino rats were injected with sodium nitrite (75 mg/kg). Quercetin (200 mg kg-1 ,- i.p.) was administrated 24 and 1 h respectively prior to sodium nitrite intoxication, hypoxia significantly decreased hemoglobin concentration, while increased expressions of HIF, Bax, Smad-2, TGF-ß, and AKT. However, administration of Quercetin played a modulatory role against the previous mentioned apoptotic factors protein expressions in all the studied tissues. On the other hand, Bcl-2 was downregulated by NaNO2 , whereas concurrent treatment with Quercetin increased its expression. It was concluded that Quercetin possesses an anti-apoptotic action induced by NaNO2 -intoxication via different mechanisms. Quercetin administration is recommended in areas of high altitudes to combat the hazard effect of hypoxia in different organs and in some diseases accompanied by hypoxic stress.

Date fruits inhibit hepatocyte apoptosis and modulate the expression of hepatocyte growth factor, cytochrome P450 2E1 and heme oxygenase-1 in carbon tetrachloride-induced liver fibrosis.

CONTEXT: Date fruits have protective effects against liver fibrosis; however their anti-apoptotic effects have not been investigated. OBJECTIVE: To investigate the modulating effects of date fruits on pro- and anti-apoptotic markers, cytochrome P450 2E1 (CYP2E1) and hepatocyte growth factor (HGF) in liver fibrosis. MATERIALS AND METHODS: Liver fibrosis was induced by injection of carbon tetrachloride (CCl4) for eight weeks. Date flesh extract (DFE) and pits extract (DPE) were taken daily concomitant with CCl4. Hepatocyte apoptosis was determined by measuring the expression of Fas, caspase-3, Bax, Bcl2 and hemeoxygenase-1 (HO-1). Hepatic levels of HGF and CYP2E1 were determined. RESULTS: Treatment with DFE and DPE significantly attenuated the elevated levels of Fas, caspase 3, Bax and CYP2E1 induced by CCl4. In addition, they alleviated the reduction in Bcl2, HGF and HO-1, the cytoprotective and anti-apoptotic factors in liver. Conclusions DFE and DPE treatment can ameliorate liver fibrosis by inhibiting hepatocyte apoptosis.

Hepatoprotective Role of α-Lipoic acid and Thymoquinone in Acetaminophen- Induced Liver Injury: Down-Regulation of COX-2 and flt-1 Expression

ABSTRACT Acetaminophen (APAP) is a widely-used analgesic, while toxic doses of which induce liver injury. Inducible cyclooxygenase-2 (COX-2) is derived prostaglandins which play an anti-inflammatory role in acetaminophen-induced hepatotoxicity. Selective activation of vascular endothelial growth factor (VEGFR1, flt -1) on endothelial cells increased mRNA levels of hepatocyte mitogens (IL-6) and hepatocyte growth factor leading to prosurvival effects on hepatocytes. The aim of this study was to compare the hepatoprotective effect of N-acetylcysteine (NAC; the antidote for APAP) with that of α-Lipoic acid (ALA) and/or Thymoquinone (THQ) either alone or in combination on liver injury induced by APAP. APAP administration elevated most of the previously measured parameters and decreased GSH, SOD, and total protein levels compared with the control group. Liver sections of H&E demonstrate liver injury characterized by centrilobular hepatocellular necrosis, COX-2, and flt-1 expressions were also increased. Treatment with all fore mentioned antioxidants ameliorated most of the altered parameters compared to APAP-treated group. Treatment with the combination of ALA and THQ was the most effective therapy in the attenuation of liver injury assessed by a decrease in ALT and ALP activities and down-regulation of COX-2 and flt-1 expression. Section of liver from rat received APAP, ALA and THQ shows a marked improvement of hepatic degeneration which restricted to few hepatocytes with mild vacuolation of their cytoplasm while the nuclei appear normal mimic to control cells. It was concluded that the natural antioxidants such as ALA and THQ, may be considered as a potential antidote in combating liver injury induced by APAP.

The antifibrotic and fibrolytic properties of date fruit extract via modulation of genotoxicity, tissue-inhibitor of metalloproteinases and nuclear factor- kappa B pathway in a rat model of hepatotoxicity.

BACKGROUND: Hepatic fibrosis and its end point; cirrhosis, are the major cause of liver failure and death in patients with chronic liver disease. Therefore, the need for an effective treatment is evident. This study was designed to assess the potential effects of aqueous extract of date fruits, either flesh (DFE) or pits (DPE), on oxidative DNA damage and liver inflammation induced by carbon tetrachloride (CCl4) and whether they are related to inhibition of nuclear factor-κB pathway. In addition, the fibrolytic potential was evaluated via measuring matrix metalloproteinase-9 and tissue inhibitor of metalloproteinases -1 and -2. METHODS: Rats were divided into the following groups: normal control, model control (CCl4 only), CCl4 + DFE, CCl4 + DPE and CCl4 + coffee. Coffee was used as a positive control. Fibrosis was induced by chronic administration of CCl4 (0.4 ml/kg) 3× a week for 8 weeks, and rats were treated with 6 ml/kg/day of DFE or DPE for 8 weeks. Liver homogenate was prepared for evaluation of oxidative stress, DNA damage, inflammatory and fibrolytic markers. Data are analyzed using one-way analysis of variance followed by a Tukey-Kramer post hoc test. RESULTS: Both DFE and DPE significantly attenuated CCl4-induced oxidative damage as indicated by reducing lipid, protein and DNA oxidation in addition to increasing the levels of hepatic catalase activity. Both extracts blocked the accumulation of collagen I in the liver and ameliorated the increased expression of collagen III and α-smooth muscle actin suggesting suppression of profibrotic response induced by CCl4. DFE and DPE also upregulated the expression of heme oxygenase-1 and attenuated the nuclear factor-κB activation and cycloxygenase-2 expression reflecting their anti-inflammatory potential. Additionally, both flesh and pits extracts attenuated the increase in the tissue inhibitor of metalloproteinases -1 and -2 suggesting their fibrolytic activity. CONCLUSION: Our data suggest that DFE or DPE can prevent liver fibrosis by suppressing genotoxicity and nuclear factor-κB inflammatory pathway and by promoting collagen degradation.

Protective Effects of Silymarin, Alone or in Combination with Chlorogenic Acid and/or Melatonin, Against Carbon Tetrachloride-induced Hepatotoxicity.

OBJECTIVE: The aim of this study was to evaluate the hepatoprotective effects of silymarin (SIL), alone and combined with chlorogenic acid (CA) and/or melatonin (ME), using a rat model of carbon tetrachloride (CCl4)-induced injury. MATERIALS AND METHODS: Hepatotoxicity was induced by a single dose of CCl4 (1 ml/kg, IP). One day after, rats were received SIL (200 mg/kg) alone or in combination with CA (60 mg/kg) and/or ME (20 mg/kg) for 21 days. RESULTS: SIL significantly decreased serum alanine aminotransferase, inflammatory cytokines, and vascular endothelial growth factor levels. Histological alterations, fibrogenesis, oxidative DNA damage, inflammatory mediators, and caspase-3 activity were significantly attenuated in SIL treated CCl4-intoxicated rats. On the other hand, cytochrome P450 2E1 activity showed a significant decrease in the liver of CCl4-intoxicated rats, an effect that was reversed following treatment with SIL. All beneficial effects of SIL were markedly potentiated when combined with CA and/or ME. CONCLUSIONS: These data indicate that SIL, alone and combined with CA and/or ME, protected the liver against CCl4-induced hepatotoxicity via attenuating inflammation, oxidative DNA damage, apoptosis, and fibrotic changes. The significantly intensified hepatoprotective effects of SIL when combined with both CA and ME suggest a possible synergism. These synergistic effects need to be further confirmed using detailed studies. SUMMARY: Silymarin, chlorogenic acid and melatonin possess in vivo hepatoprotective activitySilymarin, chlorogenic acid and melatonin attenuate fibrogenesis, oxidative DNA damage, inflammation and apoptosisChlorogenic acid and melatonin enhance the hepatoprotective effect of silymarin. Abbreviations used: SIL: silymarin, CA: chlorogenic acid, ME: melatonin, CCl4: carbon tetrachloride, CYP2E1, cytochrome P450 2E1, ALT: alanine aminotransferase, IL-6: interleukin 6, IFN-γ: interferon gamma, VEGF: vascular endothelial growth factor, TNF-α: tumor necrosis factor alpha, CRP: C-reactive protein, 8-OxodG: 8-Oxo-2'-deoxyguanosine, TGF-B1: transforming growth factor beta 1, HSCs: hepatic stellate cells.

Sitagliptin attenuates cardiomyopathy by modulating the JAK/STAT signaling pathway in experimental diabetic rats.

Sitagliptin, a dipeptidyl peptidase-4 inhibitor, has been reported to promote cardioprotection in diabetic hearts by limiting hyperglycemia and hyperlipidemia. However, little is known about the involvement of the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway modulation in the cardioprotective effects of sitagliptin. The current study aimed to investigate the protective effects of sitagliptin against diabetic cardiomyopathy (DCM), focusing on the modulation of the JAK/STAT pathway. Diabetes was induced by streptozotocin injection, and rats received sitagliptin orally and daily for 90 days. Diabetic rats exhibited hyperglycemia, hyperlipidemia, and a significant increase in heart-to-body weight (HW/BW) ratio. Serum troponin I and creatine kinase MB, cardiac interleukin-6 (IL-6), lipid peroxidation, and nitric oxide levels showed significant increase in diabetic rats. In contrast, both enzymatic and nonenzymatic antioxidant defenses were significantly declined in the heart of diabetic rats. Histopathological study revealed degenerations, increased collagen deposition in the heart of diabetic rats. Sitagliptin alleviated hyperglycemia, hyperlipidemia, HW/BW ratio, histological architecture, oxidative stress, and inflammation, and rejuvenated the antioxidant defenses. In addition, cardiac levels of pJAK2 and pSTAT3 were increased in diabetic rats, an effect which was remarkably decreased after sitagliptin treatment. In conclusion, these results confer an evidence that sitagliptin has great therapeutic potential on DCM through down-regulation of the JAK/STAT signaling pathway.