Pomegranate extract ameliorates renal ischemia/reperfusion injury in rats via suppressing NF-κB pathway.

Inflammation and oxidative stress are the major pathways involved in ischemia-reperfusion (I/R)-induced renal injury. This study was designed to evaluate the potential effect of pomegranate against I/R-induced renal injury. I/R injury was induced in nephrectomized rats by unilateral occlusion of the left renal pedicle for 45 min followed by 24 h of perfusion. Pomegranate succeeded to decrease serum levels of creatinine, potassium, and urea nitrogen, along with increasing creatinine clearance. Pomegranate also decreased I/R-induced changes in histopathological examination. Pomegranate attenuated the renal inflammatory response reflected by the suppression of nuclear factor κB p65 DNA binding activity, the upregulation of inhibitory protein kappa B-alpha mRNA expression, the downregulation of mRNA and protein expression of tumor necrosis factor α, in addition to the reduced myeloperoxidase activity and mRNA expression. Additionally, pomegranate attenuated oxidative stress likely through the modulation of lipid peroxidation and antioxidant levels reflected by the decreased MDA content and the increased glutathione level and superoxide dismutase activity. Results confirm the potential protective effect of pomegranate against I/R-induced renal injury through its anti-inflammatory and anti-oxidant effects mediated through the upregulation of inhibitory protein kappa B-alpha, the inhibition of NF-κB activity, and the associated TNF-α release, neutrophil infiltration, and oxidative stress.

Protocatechuic acid exhibits hepatoprotective, vasculoprotective, antioxidant and insulin-like effects in dexamethasone-induced insulin-resistant rats.

Protocatechuic acid (PCA), the natural phenolic antioxidant, reportedly exhibited hypoglycemic and insulin-like effects. Recent studies have reported its cardioprotective effect in glucocorticoid (GC)-induced hypertensive rats. Nevertheless, its beneficial role has not been investigated in the setting of GCs excess-induced insulin resistance. This study aimed to investigate the possible protective potential and the plausible mechanisms of pretreatment with PCA against GCs-induced insulin resistance, liver steatosis and vascular dysfunction. Insulin resistance was induced in male Wistar rats by a 7-day treatment with dexamethasone (DEX) (1 mg/kg/day, i.p.). PCA (50, 100 mg/kg/day, orally) was started 7 days before DEX administration and continued during the test period. PCA significantly and dose-dependently attenuated DEX-induced a) glucose intolerance (↓ AUCOGTT), b) hyperglycemia (↓ fasting blood glucose), c) impaired insulin sensitivity [↓fasting plasma insulin and homeostasis model assessment of insulin resistance (HOMA-IR) index)] and d) dyslipidemia (↓total cholesterol, triglycerides, low-density lipoprotein-cholesterol and very low-density lipoprotein-cholesterol). PCA mitigated DEX-induced liver steatosis with associated reduction in serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activity. Moreover, PCA ameliorated DEX-induced vascular dysfunction and enhanced ACh-induced relaxation in aortic rings. The metabolic ameliorating effects of PCA might be attributed to the enhanced insulin signaling in soleus muscles (↑AKT phosphorylation) and mitigating gluconeogenesis (↓ hepatic mRNA expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase). The vasculoprotective effect of PCA might be related to its ability to restore normal mRNA expression of [endothelial nitric oxide synthase (eNOS) and NADPH Oxidase 4 (NOX4)]. PCA restored normal oxidative balance [↓ oxidant species, malondialdehyde (MDA) and (↑ antioxidant superoxide dismutase (SOD)]. The findings herein reveal for the first time that PCA may be taken as a supplement with GCs to limit their metabolic and vascular side effects through its hypoglycemic, insulin-sensitizing, hypolipidemic and antioxidant effects.

Impact of interferon ß-1b, interferon ß-1a and fingolimod therapies on serum interleukins-22, 32α and 34 concentrations in patients with relapsing-remitting multiple sclerosis.

Interleukins (ILs)-22, 32α and 34 were monitored in the sera of relapsing-remitting multiple sclerosis (RRMS) patients at different time intervals with or without interferon ß-1b, interferon ß-1a and fingolimod treatments. The results showed that sera of untreated RRMS patients were statistically higher in concentration of IL-22 (P < .001), but not IL-32α and IL-34, than those of healthy individuals. Interestingly, interferon ß-1b, interferon ß-1a and fingolimod treatments led to a significant decrease of serum concentrations of ILs-22 and 32α, but not 34, at 6 and 12 months of treatment, compared to their initial concentrations before initiating therapy. The correlation analysis revealed that the changes of serum IL-22 (r = 0.814) and, to a lesser extent, IL-32α (r = 0.381) concentrations were positively correlated with those of expanded disability status score. In conclusion, serum IL-22 concentration may be a potential marker for MS disease severity and efficacy of treatment.

Comparison of the effects of sulforaphane and pioglitazone on insulin resistance and associated dyslipidemia, hepatosteatosis, and endothelial dysfunction in fructose-fed rats.

The purpose of this work was to compare the influences of sulforaphane (SFN) to those of the standard insulin sensitizer pioglitazone (PIO) on high fructose diet (HFrD)-induced insulin resistance, dyslipidemia, hepatosteatosis, and vascular dysfunction in rats. Male Sprague Dawley rats (150-200 g) were fed on a standard diet (control) or a high fructose diet (HFrD, 60% w/w fructose) for 60 days. From day 16, two subgroups of HFrD-fed rats received either SFN (0.5 mg/kg/day, orally) or PIO (5 mg/kg/day, orally) along with HFrD until the end of the experiment. Fructose-fed rats showed significant decreases in food intake, body weight and feeding efficiency; effects that were not altered by either treatment. Data from insulin tolerance test (ITT), oral glucose tolerance test (OGTT), and HOMA-IR and HOMA-ß indices demonstrated impaired insulin sensitivity and glucose utilization in HFrD-fed rats. SFN and PIO treatments significantly reduced OGTTAUC (Glass's Delta values = 1.12 and 0.84, respectively), decreased ITTAUC (Glass's Delta values = 1.05 and 0.71, respectively), significantly diminished HOMA-IR index (by 55.6% and 77.6%, respectively), and increased HOMA-ß value (by 1.8 and 1.3 fold, respectively) compared to the HFrD rats. Moreover, SFN and PIO ameliorated hepatic oxidative stress and reduced serum levels of C-reactive protein and lactate dehydrogenase in HFrD-fed rats. Furthermore, SFN and PIO administrations improved insulin resistance-associated heaptosteatosis and enhanced vascular responsiveness to acetylcholine-induced relaxations. However, only SFN was able to enhance serum HDL-C levels in HFrD group. These finding suggests that SFN elicited insulin-sensitizing, hepatoprotective, and vasculoprotective effects in HFrD insulin-resistant rats that were comparable to those exerted by PIO.

Modulatory role of gabapentin against ovalbumin-induced asthma, bronchial and airway inflammation in mice.

Allergic asthma is a type of chronic immune-mediated inflammatory lung disorders with constantly increased worldwide prevalence. Gabapentin is an L-type calcium channel blocker used essentially as antiepileptic and recently has been indicated for management of post-operative and neuropathic pains as an anti-inflammatory. The current study was conducted to evaluate the anti-inflammatory and anti-allergic properties of gabapentin in a mouse-model of Ovalbumin-induced allergic asthma. Mice received OVA (10 mg) adsorbed on Al(OH)3 on days 0 and 7 and were challenged by exposure to nebulized OVA solution (1%) form days 14-16. Asthma induction was associated with significant biochemical, oxidative and inflammatory imbalance. Daily oral gabapentin (50 mg/kg), significantly reduced lung inflammatory cells counts', serum LDH and catalase activities and lung/body weight index. Moreover, gabapentin significantly increased lung GSH concentration and enhanced SOD activity. Lung contents of TNFα, IL-4 and IL-13 significantly declined as well. IL-13; is the major contributor to airway hyper-responsiveness; the charetrestic hallmark of asthma and IL-4; a major chemoattractant cytokine. Lung histopathology significantly improved parallel to the biochemical improvements. In conclusion; Gabapentin's modulatory effect on IL-4, IL-13 and TNFα activities accounts for the observed anti-inflammatory and anti-allergic properties.

Comparison of lactate and ß-hydroxybutyrate in the treatment of concanavalin-A induced hepatitis.

Simple metabolites released during physical exercise and fasting like lactate (Lac) and ß-hydroxybutyrate (BHB) have recently been shown to possess anti-inflammatory properties. However, the effects of these metabolites in immune mediated hepatitis are still unknown. Accordingly, we investigated the role of Lac, BHB and their combination on experimentally induced hepatic inflammation. Adult male mice were administered concanavalin A (Con A, 15 mg/kg, intravenous) for 12 h. In the treatment groups, mice were treated 1 h after Con A-intoxication with Lac (500 mg/kg, intraperitoneal), BHB (300 mg/kg, intraperitoneal) and their combination. The results demonstrated that Lac and BHB, especially when combined together, alleviated Con A-induced hepatocellular injury (ALT, AST and LDH) and necrosis (hematoxylin-eosin and electron microscopy). These beneficial effects correlated with attenuating Con A-induced elevation in hepatic oxidative stress parameters (MDA and NOx). Mechanistically, administration of Lac and BHB led to inhibition of Con A-induced phosphorylation of JNK and AMPK proteins in the liver to the same extent. These effects were concordant with curbing Con A-mediated overexpression of the pro-inflammatory cytokines TNF-α, IL-6 and IL-12 and activation of the transcription factor NF-κB. The marked anti-inflammatory properties of combining Lac and BHB were attributed to their cooperation in repressing immune cells (monocytes and neutrophils) infiltration to the liver. Unlike BHB, Lac administration markedly induced the reparative STAT3 and ERK phosphorylation in the livers of Con A-intoxicated mice at the early time point. In conclusion, the simultaneous use of Lac and BHB might be an auspicious strategy for limiting immune mediated hepatitis.

Crocin modulates IL-4/IL-13 signaling and ameliorates experimentally induced allergic airway asthma in a murine model.

Allergic asthma is a chronic respiratory disease with a prevalent T helper (Th2)-mediated immune reaction. Crocin, the major bioactive constituent of saffron, has been reported in multiple studies to have numerous pharmacological activities, including prominent anti-oxidant activities. In the current study, the anti-asthmatic potential of crocin was evaluated. Adult male Swiss Albino mice were administered 10mg of ovalbumin (OVA) mixed with 1mg of aluminum hydroxide intraperitoneally on days 0 and 7 and were administered crocin (25mg/kg) orally daily for 16days. Asthma progression was associated with significant increase in the lung/body weight index, inflammatory cell counts in bronchoalveolar lavage fluid (BALF), lung total protein content, and serious index of lung permeability, indicating pulmonary edema with accumulation of serous fluids within the lungs. Serum lactate dehydrogenase (LDH) activity and lung malondialdehyde (MDA) content were significantly increased, while lung superoxide dismutase (SOD) activity, reduced glutathione (GSH) levels, and serum and lung catalase activities were significantly decreased. These changes reflect significant pulmonary inflammation with concomitant disturbance of oxidant/antioxidant homeostasis. Moreover, tumor necrosis factor (TNF)-α, interleukin (IL)-4, and IL-13 contents in the lung were also significantly high after OVA sensitization. Crocin treatment significantly alleviated the OVA-induced allergic asthma-associated alterations in inflammatory and oxidative stress biomarkers. Crocin enhanced anti-oxidant defenses, reduced the incidence of oxidative stress, and restored pro-inflammatory cytokines to normal levels. Histopathological analysis showed significant lung improvement in crocin-treated mice. In conclusion, crocin showed a significant protective effect against allergic asthma progression, which was associated with down-regulation of inflammatory cytokine expression and restoration of oxidant/antioxidant homeostasis.

Repression of acetaminophen-induced hepatotoxicity by a combination of celastrol and brilliant blue G.

The sterile inflammatory response is an eminent contributor to acetaminophen (APAP)-hepatotoxicity in humans. Recent advances unraveled an axial role of the NLRP3-inflammasome in APAP-post injury inflammation. Nevertheless, the role of signaling events preceded the NLRP3-inflammasome activation, like the transcription factor NF-κB and the purinergic receptor P2X7, is still unclear and needs further elucidation. Here, we investigated the pharmacological inhibition of these upstream signaling molecules by celastrol and brilliant blue G (BBG) (separately or simultaneously) in APAP-hepatotoxicity in mice. The results indicated that both celastrol and BBG pretreatments, especially when combined together, curbed APAP-induced hepatocellular injury (ALT, AST and LDH) and death (necrosis and apoptosis). The underlying mechanisms of protection of such combination against APAP-challenge were attributed to their efficient cooperation in: i) preventing the consumption of hepatic antioxidants (reduced glutathione and superoxide dismutase); ii) limiting the overproduction of lipid peroxidation aldehydes (malondialdehyde and 4-hydroxynonenal) and total nitrate/nitrite products; iii) attenuating the inflammatory cells accumulation in the liver, as evidenced by reducing the number of F4/80 positive cells/field in immunostaining and myeloperoxidase activity; iv) reversing the dysregulation in production of pro-inflammatory (TNF-α, IL-17A and IL-23) and anti-inflammatory (IL-10) cytokines; and v) enhancing the reparative capacity of injured hepatocytes, as demonstrated by increasing the percentage of PCNA positive hepatocytes per field of immunostaining. In conclusion, this murine study elicits a potential clinical applicability and therapeutic utility of celastrol and BBG combination in human cases of APAP-overdose hepatotoxicity.

Sulforaphane improves dysregulated metabolic profile and inhibits leptin-induced VSMC proliferation: Implications toward suppression of neointima formation after arterial injury in western diet-fed obese mice.

Sulforaphane (SFN), a dietary phase-2 enzyme inducer that mitigates cellular oxidative stress through nuclear factor erythroid 2-related factor 2 (Nrf2) activation, is known to exhibit beneficial effects in the vessel wall. For instance, it inhibits vascular smooth muscle cell (VSMC) proliferation, a major event in atherosclerosis and restenosis after angioplasty. In particular, SFN attenuates the mitogenic and pro-inflammatory actions of platelet-derived growth factor (PDGF) and tumor necrosis factor-α (TNFα), respectively, in VSMCs. Nevertheless, the vasoprotective role of SFN has not been examined in the setting of obesity characterized by hyperleptinemia and insulin resistance. Using the mouse model of western diet-induced obesity, the present study demonstrates for the first time that subcutaneous delivery of SFN (0.5mg/Kg/day) for~3weeks significantly attenuates neointima formation in the injured femoral artery [↓ (decrease) neointima/media ratio by~60%; n=5-8]. This was associated with significant improvements in metabolic parameters, including ↓ weight gain by~52%, ↓ plasma leptin by~42%, ↓ plasma insulin by~63%, insulin resistance [↓ homeostasis model assessment of insulin resistance (HOMA-IR) index by~73%], glucose tolerance (↓ AUCGTT by~24%), and plasma lipid profile (e.g., ↓ triglycerides). Under in vitro conditions, SFN significantly decreased leptin-induced VSMC proliferation by~23% (n=5) with associated diminutions in leptin-induced cyclin D1 expression and the phosphorylation of p70S6kinase and ribosomal S6 protein (n=3-4). The present findings reveal that, in addition to improving systemic metabolic parameters, SFN inhibits leptin-induced VSMC proliferative signaling that may contribute in part to the suppression of injury-induced neointima formation in diet-induced obesity.

Comparison of the effects of levocetirizine and losartan on diabetic nephropathy and vascular dysfunction in streptozotocin-induced diabetic rats.

This work was designed to investigate the effects of levocetirizine, a histamine H1 receptor antagonist, on diabetes-induced nephropathy and vascular disorder, in comparison to an angiotensin II receptor antagonist, losartan. Diabetes was induced in male Sprague Dawley rats by a single intraperitoneal injection of streptozotocin (50mg/kg). Diabetic rats were divided into three groups; diabetic, diabetic-levocetirizine (0.5mg/kg/day) and diabetic-losartan (25mg/kg/day). Treatments were started two weeks following diabetes induction and continued for additional eight weeks. At the end of the experiment, urine was collected and serum was separated for biochemical measurements. Tissue homogenates of kidney and aorta were prepared for measuring oxidative stress, nitric oxide (NO), transforming growth factor-ß1 (TGF-ß1) and tumor necrosis factor-α (TNF-α). Moreover, histological analyses were conducted and aortic vascular reactivity was investigated. Levocetirizine improved renal function in diabetic rats (evidenced by mitigation of diabetes-induced changes in kidney to body weight ratio, serum albumin, urinary proteins and creatinine clearance). Moreover, levocetirizine attenuated the elevated renal levels of TNF-α and TGF-ß1, ameliorated renal oxidative stress and restored NO bioavailability in diabetic kidney. These effects were comparable to or surpassed those produced by losartan. Moreover, levocetirizine, similar to losartan, reduced the enhanced responsiveness of diabetic aorta to phenylephrine. Histological evaluation of renal and aortic tissues further confirmed the beneficial effects of levocetirizine on diabetic nephropathy and revealed a greater attenuation of diabetes-induced vascular hypertrophy by levocetirizine than by losartan. In conclusion, levocetirizine may offer comparable renoprotective effect to, and possibly superior vasculoprotective effects than, losartan in streptozotocin-diabetic rats.

Pomegranate protects liver against cecal ligation and puncture-induced oxidative stress and inflammation in rats through TLR4/NF-κB pathway inhibition.

Acute liver injury secondary to sepsis is a major challenge in intensive care unit. This study was designed to investigate potential protective effects of pomegranate against sepsis-induced acute liver injury in rats and possible underlying mechanisms. Pomegranate was orally given (800mg/kg/day) for two weeks before sepsis induction by cecal ligation and puncture (CLP). Pomegranate improved survival and attenuated liver inflammatory response, likely related to downregulation of mRNA expression of toll like recptor-4, reduced nuclear translocation and DNA binding activity of proinflammatory transcription factor NF-κB subunit p65, decreased mRNA and protein expression of tumor necrosis factor-alpha and reduction in myeloperoxidase activity and mRNA expression. Pomegranate also decreased CLP-induced oxidative stress as reflected by decreased malondialdehyde content, and increased reduced glutathione level and superoxide dismutase activity. These results confirm the antiinflammatory and antioxidant effects of pomegranate in CLP-induced acute liver injury mediated through inhibiting TLR4/NF-κB pathway, lipid peroxidation and neutrophil infiltration.

The ergogenic supplement ß-hydroxy-ß-methylbutyrate (HMB) attenuates insulin resistance through suppressing GLUT-2 in rat liver.

This study investigates the effect of the ergogenic supplement ß-hydroxy-ß-methylbutyrate (HMB) on insulin resistance induced by high-fructose diet (HFD) in rats. Male Sprague Dawley rats were fed 60% HFD for 12 weeks and HMB (320 mg·kg(-1)·day(-1), orally) for 4 weeks. HFD significantly increased fasting insulin, fasting glucose, glycosylated hemoglobin (HBA1C), liver glycogen content, and homeostasis model assessment of insulin resistance (HOMA-IR) index, while it decreased glucose and insulin tolerance. Furthermore, HFD significantly increased serum triglycerides (TG), low density lipoprotein cholesterol (LDL-C), and very low density lipoprotein cholesterol (VLDL-C) levels, while it significantly decreased high density lipoprotein cholesterol (HDL-C). Moreover, HFD significantly increased mRNA expression of glucose transporter type-2 (GLUT-2), the mammalian target of rapamycin (mTOR), and sterol regulatory element-binding protein-1c (SREBP-1c) but decreased peroxisome proliferator-activated receptor-alpha (PPAR-α) in liver. Aortic relaxation to acetylcholine (ACh) was impaired and histopathology showed severe hepatic steatosis. HMB significantly increased insulin tolerance and decreased fasting insulin, HOMA-IR, HBA1C, hepatic glycogen content, serum TG, LDL-C, and VLDL-C. Additionally, HMB enhanced ACh-induced relaxation, ameliorated hepatic steatosis, and decreased mRNA expression of GLUT-2. In conclusion, HMB may attenuate insulin resistance and hepatic steatosis through inhibiting GLUT-2 in liver.

Attenuation of insulin resistance in rats by agmatine: role of SREBP-1c, mTOR and GLUT-2.

Insulin resistance is a serious health condition worldwide; however, its exact mechanisms are still unclear. This study investigates agmatine (AGM; an endogenous metabolite of L-arginine) effects on insulin resistance induced by high fructose diet (HFD) in rats and the possible involved mechanisms. Sprague Dawley rats were fed 60% HFD for 12 weeks, and AGM (10 mg/kg/day, orally) was given from week 9 to 12. AGM significantly reduced HFD-induced elevation in fasting insulin level, homeostasis model assessment of insulin resistance (HOMA-IR) index and liver glycogen content from 3.44-, 3.62- and 2.07- to 2.59-, 2.78- and 1.3-fold, respectively, compared to the control group, while it increased HFD-induced reduction in glucose tolerance. Additionally, AGM significantly decreased HFD-induced elevation in serum triglycerides, low density lipoprotein cholesterol and very low density lipoprotein cholesterol levels from 3.18-, 2.97- and 4.75- to 1.25-, 1.25- and 1.07-fold, respectively, compared to control group. Conversely, AGM had no significant effect on HFD-induced changes in fasting glucose, glycosylated hemoglobin, insulin tolerance and high density lipoprotein cholesterol. Furthermore, AGM significantly reduced HFD-induced elevation in mRNA expression of glucose transporter type-2 (GLUT-2), mammalian target of rapamycin (mTOR) and sterol regulatory element-binding protein-1c (SREBP-1c) without affecting that of peroxisome proliferator-activated receptor-alpha (PPAR-α) in the liver. Additionally, AGM enhanced ACh-induced aortic relaxation and attenuated liver steatosis induced by HFD. In conclusion, AGM may have a therapeutic potential in insulin resistance through suppressing SREBP-1c, mTOR and GLUT-2 in liver.

Levocetirizine ameliorates high fructose diet-induced insulin resistance, vascular dysfunction and hepatic steatosis in rats.

This study investigates the possible protective effects of levocetirizine against fructose-induced insulin resistance, hepatic steatosis and vascular dysfunction, in comparison to pioglitazone, a standard insulin sensitizer. Male Sprague Dawley rats (150-200 g) were divided into 4 groups. Three groups were fed on high fructose diets (HFD) containing 60% w/w fructose, while the fourth control group was fed on standard laboratory food for 8 weeks. AUCOGTT, AUCITT, fasting glucose, HOMA-IR, hepatic glutathione (GSH) and malondialdehyde (MDA) levels, serum total cholesterol, LDL-C, C-reactive protein (CRP) level and lactate dehydrogenase (LDH) activity and liver steatosis scores were significantly higher in HFD group compared to control group. Moreover, body weight gain, food intake, feeding efficiency, HOMA-ß, Emax and pEC50 of acetylcholine-induced relaxations of aortic rings and hepatic superoxide dismutase (SOD) activity were significantly lower in HFD group than in control group. Treatment with levocetirizine caused significant decreases in AUCOGTT, AUCITT, HOMA-IR, hepatic GSH and MDA levels and serum CRP level and LDH activity and significant increases in hepatic SOD activity and HOMA-ß when compared with the HFD group. Although levocetirizine failed to alter TC and LDL-C levels, it produced a significant increase in HDL-C level relative to control group. Levocetirizine was also able to improve acetylcholine-induced relaxations of aortic rings, indicating a protective effect against insulin resistance-induced endothelial damage comparable to that offered by pioglitazone. Moreover, levocetirizine substantially attenuated insulin resistance-associated liver macrovesicular steatosis. These findings demonstrate that levocetirizine ameliorates insulin resistance, improves glucose tolerance and attenuates insulin resistance-linked hepatic steatosis and vascular damage.

Modulation of thioacetamide-induced liver fibrosis/cirrhosis by sildenafil treatment.

Sildenafil citrate is a phosphodiesterase-5 inhibitor, approved for the treatment of erectile dysfunction. It enhances nitric-oxide-induced vasodilatation and it promotes angiogenesis. A relationship between angiogenesis and hepatic fibrosis has long been speculated, where the 2 are believed to progress together. In this study, the ability of sildenafil (10 mg·(kg body mass)(-1), orally, once daily) to prevent and also reverse liver fibrosis/cirrhosis experimentally induced by thioacetamide injection (200 mg·kg(-1), intraperitoneal (i.p.), 3 times·week(-1)) in male Sprague-Dawley rats has been investigated. Sildenafil administration, either to prevent or to reverse liver fibrosis/cirrhosis significantly improved the estimated hepatic functions, reduced hepatic hydroxyproline and, in turn, hepatic collagen content, as well as reducing serum levels of the pro-fibrogenic mediator transforming growth factor ß1. In co-ordination with such improvement, fibrosis grades declined and fibrosis retracted. Herein, the observed results provide evidence for the potential therapeutic efficacy of sildenafil as an antifibrotic agent.

Modulation of cyclophosphamide-induced early lung injury by allicin.

CONTEXT: Cyclophosphamide (CP) causes lung injury in rats through its ability to generate free radicals with subsequent epithelial and endothelial cell damage. OBJECTIVE: This study was conducted to assess whether allicin can ameliorate CP-induced early lung injury in rats. MATERIALS AND METHODS: Male Sprague Dawely rats were divided into four groups. Group I was the control group. Group II received allicin (50 mg/kg/d, p.o.) for 14 consecutive days. Group III was injected once with CP (150 mg/kg, i.p.). Group IV received allicin for seven consecutive days, before and after CP injection (150 mg/kg, i.p.). The parameters of study were serum biomarkers, lung tissue antioxidant profile and histopathological changes in lung tissue. RESULTS: A single intraperitoneal injection of CP markedly altered the levels of several biomarkers in lung homogenates. Significant increases in lung content of lipid hydroperoxides were seen that paralleled the decreased levels of total reduced glutathione. Superoxide dismutase activity (SOD) was significantly increased. CP increased the level of serum biomarkers; total protein, lactate dehydrogenase (LDH) and tumor necrosis factor-alpha (TNF-α). Pretreatment of rats daily with oral allicin seven days prior to and seven days after CP inject significantly inhibited the development of lung injury, prevented the alterations in lung and serum biomarkers associated with inflammatory reactions, with less lipid peroxidation (LP) and restoration of antioxidants. Moreover, allicin attenuated the secretion of proinflammatory cytokine, TNF-α expression in rat serum. In addition, allicin effectively blunted CP-induced histopathological changes in lung tissue. DISCUSSION AND CONCLUSION: Our results suggest that allicin is efficient in blunting CP-induced pulmonary damage.

Thymoquinone attenuates cyclophosphamide-induced pulmonary injury in rats.

OBJECTIVE: Antioxidant therapy may be useful in diseases with impaired oxidant-antioxidant balance. This study was designed to examine the effects of thymoquinone (TQ), an anti-inflammatory, antioxidant agent against cyclophosphamide (CP)-induced pulmonary oxidative damage. MATERIALS AND METHODS: Male Sprague-Dawley rats were categorized into four groups. Group I was control. Group II received TQ (100 mg/kg/day, p.o.) for 14 consecutive days. Group III was injected once with CP (150 mg/kg, i.p.). Group IV received TQ for 7 consecutive days, before and after CP injection. The parameters of study were tissue oxidant/antioxidant biomarkers and histological changes in rat lungs. RESULTS: A single intraperitoneal injection of CP markedly altered the levels of several biomarkers in lung homogenates. Significant increases in the content of lipid peroxides in lung were seen that paralleled the decreased levels of reduced glutathione. Cyclophosphamide increased the level of serum biomarkers: total protein, lactate dehydrogenase, and tumor necrosis factor-alpha (TNF-α). Treatment of rats with TQ 7 days before and after cyclophosphamide injection significantly attenuated the alterations in lung and serum biomarkers associated with inflammatory reactions, with less lipid peroxidation and restoration of antioxidants. Moreover, TQ attenuated the secretion of pro-inflammatory cytokine, TNF-α in rat serum. In addition, TQ effectively alleviated CP-induced histopathological changes in lung tissue. DISCUSSION AND CONCLUSION: Our results suggest that TQ produces a protective mechanism against CP-induced pulmonary damage and suggest a role of oxidative stress and inflammation in the pathogenesis.

Influence of inhaled beclomethasone and montelukast on airway remodeling in mice.

This study examined the effect of montelukast and beclomethasone on airway remodeling in murine model of asthma. Mice were sensitized by i.p. injection of ovalbumin (OVA) on days 0 and 14, and then challenged by nebulization of 1% OVA 3 days/week for 6 or 10 weeks. Results of 6-week OVA-challenged group showed moderate inflammation, but the 10-week OVA-challenged group exhibited mild inflammation. The OVA challenge (6 and 10 weeks) exhibited marked airway fibrosis, illustrated by significant increase in goblet cell hyperplasia and epithelial thickness, increased lung content of collagen and transforming growth factor-ß(1), together with a decrease in nitric oxide production; also, there was an increase in bronchoalveolar lavage fluid level of interleukin-13. Administration of montelukast or beclomethasone before each OVA challenge was capable of restoring most of the measured parameters to near normal levels. Inhalation of beclomethasone has a similar role in airway remodeling as montelukast, but its effects in regulating inflammatory changes is less pronounced than montelukast.

Tranilast ameliorates impaired hepatic functions in Schistosoma mansoni-infected mice.

The ability of tranilast, a mast cell stabilizer and anti-transforming growth factor(ß) (TGF(ß)) to improve impaired hepatic functions in Schistosoma mansoni (S. mansoni)-infected mice, was investigated, providing the first evidence on the ability of tranilast to improve hepatic impairment due to schistosomal infection. Tranilast had significant beneficial effects against progression of hepatic fibrosis in S. mansoni-infected mice treated with praziquantel and those untreated. Different aspects of drug activity were investigated. Its effect on serum liver functions was evaluated by estimating: alanine aminotransferase, aspartate aminotransferase, total bilirubin, alkaline phosphatase and albumin. Its effect on the extent of liver fibrosis, through estimation of hepatic hydroxyproline and hepatic collagen content in liver hydrolysates, was also evaluated. Also, the expression of profibrogenic mediators, such as serum TGF(ß1), was estimated. Finally, the effect on S. mansoni infection itself was studied, via histopathological examination of liver specimens stained with both hematoxylin-eosin and Masson's trichome stains. Tranilast ameliorated the harmful effects of S. mansoni infection on the liver. Such action was manifested in its significant ability to improve impaired hepatic functions, reduce histopathological changes, lower hepatic collagen content and finally reduce serum TGF(ß1) levels. The beneficial effect of tranilast may be in part due to its ability to reduce the production of profibrogenic mediators in the infected animals by improving the host immune response or by interfering with critical steps in the fibrogenic cascade.

Protective potential of MMR vaccine against complete Freund's adjuvant-induced inflammation in rats.

The aim of the present study was to investigate the effect of MMR vaccine on inflammation which was induced by complete Freund's adjuvant (CFA) in male Sprague-Dawley rats. Rats were randomly divided into the control, CFA, MMR and CFA + MMR groups. Inflammatory symptoms such as paw oedema was measured in CFA-injected rats' paw. Body weight changes and alterations in some haematological parameters and oxidative stress markers following CFA injection were checked. In CFA-inflammed rats, there was a significant increase in rat paw thickness and decrease in body weight increment. MMR exhibited a significant anti-inflammatory effect as manifested by reduction in paw thickness and normal gain in body weight when administered 1 week prior to induction of inflammation. The altered haematological parameters (TLC) and oxidative stress markers (MDA, GSH, SOD) in the inflammed rats were significantly brought back to near normal by MMR treatment. In conclusion, MMR vaccine showed a reduction in rat paw thickness and it could significantly normalize the haematological and biochemical abnormalities in CFA-induced inflammatory pain model in rats. Our data suggested that MMR could be a potential protective agent against certain types of inflammatory pain. Further histopathological and radiological studies are required to confirm the possibility of developing novel therapeutic vaccines against some forms of arthritis.