Evening primrose oil and celecoxib inhibited pathological angiogenesis, inflammation, and oxidative stress in adjuvant-induced arthritis: novel role of angiopoietin-1.

Rheumatoid arthritis is a chronic inflammatory disease characterized by overproduction of inflammatory mediators along with undermined oxidative defensive mechanisms. Pathological angiogenesis was found to play a critical role in the progression of this disease. The current study was carried out to evaluate the anti-angiogenic, anti-inflammatory, and anti-oxidant effects of evening primrose oil (EPO), rich in gamma linolenic acid (GLA), either alone or in combination with aspirin or celecoxib, on adjuvant-induced arthritis. Arthritis was induced by subcutaneous injection of complete Freund's adjuvant (CFA) in the right hind paw of male albino rats. All treatments were administered orally from day 0 (EPO, 5 g/kg b.w.) or day 4 (celecoxib, 5 mg/kg; aspirin, 150 mg/kg) till day 27 after CFA injection. In the arthritic group, the results revealed significant decrease in the body weight and increase in ankle circumference, plasma angiopoietin-1 (ANG-1) and tumor necrosis factor-alpha (TNF-α) levels. Anti-oxidant status was suppressed as manifested by significant decline in reduced glutathione content along with decreased enzymatic activity of superoxide dismutase and increased lipid peroxidation. Oral administration of EPO exerted normalization of body weight, ANG-1, and TNF-α levels with restoration of activity as shown by reduced malondialdehyde levels. Moreover, histopathological examination demonstrated that EPO significantly reduced the synovial hyperplasia and inflammatory cells invasion in joint tissues, an effect that was enhanced by combination with aspirin or celecoxib. The joint use of GLA-rich natural oils, which possess anti-angiogenic, anti-inflammatory, and anti-oxidant activities, with traditional analgesics represents a promising strategy to restrain the progression of rheumatoid arthritis.

Deletion of thioredoxin-interacting protein preserves retinal neuronal function by preventing inflammation and vascular injury.

BACKGROUND AND PURPOSE: Retinal neurodegeneration is an early and critical event in several diseases associated with blindness. Clinically, therapies that target neurodegeneration fail. We aimed to elucidate the multiple roles by which thioredoxin-interacting protein (TXNIP) contributes to initial and sustained retinal neurodegeneration. EXPERIMENTAL APPROACH: Neurotoxicity was induced by intravitreal injection of NMDA into wild-type (WT) and TXNIP-knockout (TKO) mice. The expression of apoptotic and inflammatory markers was assessed by immunohistochemistry, elisa and Western blot. Microvascular degeneration was assessed by periodic acid-Schiff and haematoxylin staining and retinal function by electroretinogram. KEY RESULTS: NMDA induced early (1 day) and significant retinal PARP activation, a threefold increase in TUNEL-positive nuclei and 40% neuronal loss in ganglion cell layer (GCL); and vascular permeability in WT but not TKO mice. NMDA induced glial activation, expression of TNF-α and IL-1ß that co-localized with Müller cells in WT but not TKO mice. In parallel, NMDA triggered the expression of NOD-like receptor protein (NLRP3), activation of caspase-1, and release of IL-1ß and TNF-α in primary WT but not TKO Müller cultures. After 14 days, NMDA induced 1.9-fold microvascular degeneration, 60% neuronal loss in GCL and increased TUNEL-labelled cells in the GCL and inner nuclear layer in WT but not TKO mice. Electroretinogram analysis showed more significant reductions in b-wave amplitudes in WT than in TKO mice. CONCLUSION AND IMPLICATIONS: Targeting TXNIP expression prevented early retinal ganglion cell death, glial activation, retinal inflammation and secondary neuro/microvascular degeneration and preserved retinal function. TXNIP is a promising new therapeutic target for retinal neurodegenerative diseases.

15-PGDH inhibitors: the antiulcer effects of carbenoxolone, pioglitazone and verapamil in indomethacin induced peptic ulcer rats.

BACKGROUND AND AIM: 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is the enzyme responsible for prostaglandins (PGs) metabolism. PGs have an important role in the protection of stomach mucosa against destructive stimuli. The aim of the present study is to investigate the inhibitory effect of carbenoxolone, pioglitazone and verapamil on 15-PGDH enzyme. MATERIALS AND METHODS: The experiments were carried out in the Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt from May 2011 to August 2011. Adult male albino rats were fasted for 18 hours before administration of high dose of indomethacin (30 mg/kg, p.o.), except for the negative control group which received saline only, followed by pyloric ligation to induce acute gastric ulcers. The rats were pretreated orally with saline, pioglitazone (20 mg/kg), verapamil (25 mg/kg), carbenoxolone (30 mg/kg) or their combinations 30 minutes before indomethacin. The rats were sacrificed after four hours of pyloric ligation. The effects of the previous treatments on the ulcer index (Ui), the microscopic appearance of gastric mucosa, the gastric acid output, the gastric barrier mucus content, and 15-PGDH enzyme activity were determined. RESULTS: Indomethacin resulted in severe ulceration and increased gastric acid output (p < 0.05) compared to negative control. The rats pretreated with carbenoxolone, pioglitazone, verapamil had reduced ulcer index, gastric acid output and 15-PGDH activity (p < 0.05) compared to either indomethacin group or the negative control group. Individual treatments with carbenoxolone, pioglitazone or verapamil increased gastric barrier mucus (p < 0.05) compared to either indomethacin group or the negative control group. The combinations of verapamil with either carbenoxolone or pioglitazone caused further reduction in ulcer index, gastric acid output and 15-PGDH activity (p < 0.05), while causing further increase in gastric barrier mucus (p < 0.05) compared to their respective individual treatment group. CONCLUSIONS: The antiulcer properties of pioglitazone and verapamil are, in part, consequences of their inhibitory effect on the enzyme 15-PGDH, responsible for PGs degradation, and the resultant prolongation of PGE2 biological activity in rat stomach mucosa.

Eicosapentaenoic acid ablates valproate-induced liver oxidative stress and cellular derangement without altering its clearance rate: dynamic synergy and therapeutic utility.

The omega-3 fatty acid eicosapentaenoic acid (EPA) is a superb nature's medicine, with still unfolding health benefits. Because hepatotoxicity is a prominent adverse drug reaction, we currently attempted a new approach in which EPA was challenged to both alleviate hepatotoxicity and provide synergy with anticonvulsant effects of valproate (VPA). Besides, we verified whether EPA may kinetically modulate the clearance rate of VPA. VPA (500mg/kg p.o., for 2weeks) caused rat hepatotoxicity that was manifested as notable (2- to 4-fold) rise in serum liver enzymes (GGT, ALT, and ALP), increased hepatic levels of lipid peroxides and TNF-α (3- and 7-fold) and activity of myeloperoxidase (MPO, 4-fold), lowering of serum albumin (42%), and depletion of liver reduced glutathione (GSH, 36%). Furthermore, histopathologic examination revealed hepatocellular degeneration, focal pericentral necrosis, infiltration of inflammatory cells, and steatosis. Joint treatment with EPA (300mg/kg) blunted the oxidative stress, TNF-α levels and MPO activity, while enhanced levels of serum albumin and hepatic GSH. EPA also ameliorated most of the hepatocellular anomalies evoked by VPA. Additionally, in a mouse PTZ convulsion model, EPA markedly augmented the anticonvulsant effects of VPA far beyond their single responses. On the other hand, pharmacokinetic analyses revealed that joint EPA administration had no effect on serum VPA concentrations. Collectively, results demonstrate for the first time that the ω-3 FA (EPA) markedly alleviated VPA-induced hepatotoxicity, oxidative stress, and inflammation, while enhanced its anticonvulsant effects without altering its clearance. Therapeutically, these protective and synergy profiles for EPA foster a more safe and efficacious drug combination regimen than VPA.

Evaluation of renal protective effects of the green-tea (EGCG) and red grape resveratrol: role of oxidative stress and inflammatory cytokines.

Epigallocatechin-gallate (EGCG) and resveratrol (RSVL) are two of the most promising natural medicines. We verified their capacity to ameliorate cisplatin (CP)-induced disruption of renal glomerular filtration rate (GFR) in rats, and sought the mediatory involvement of lipid peroxidation (malondialdehyde [MDA]-level) and inflammatory cytokine (TNF-α) therein. CP (10 mg kg⁻¹), a single i.p. dose, disrupted GFR (11-fold-rise in proteinuria, 2-5-fold rise in serum creatinine/urea levels) after 7 days, and killed all animals after 10 days. Kidney-homogenates from CP-treated rats displayed higher MDA and TNF-α, but lower reduced-glutathione (GSH) levels. Rats treated with EGCG (50 mg kg⁻¹, but not 25 mg kg⁻¹) had no fatalities and showed significantly-recovered GFR; while their kidney-homogenates had markedly reduced MDA, TNF-α and enhanced GSH levels at 7 days. Conversely, RSVL or quercetin (25, 50 mg kg⁻¹) neither improved GFR nor reduced (MDA)/TNF-α levels after 7 days. Resuming treatment with 50 mg kg⁻¹ for 10 days rescued only 25% of animals (p > 0.05). Correlation studies showed a significant association between creatinine level, and each of MDA (r = 0.91), GSH (r = -0.87), and TNF-α (0.91). The study showed for the first time that EGCG, unlike RSVL, can protect against CP-induced nephrotoxicity. At the molecular level, CP triggers a high level of oxidative stress and systemic inflammation, events that were all abrogated with EGCG; better than RSVL or quercetin.

Renal Doppler ultrasonography in children with equivocal obstructive uropathy: effect of intravenous normal saline fluid load and frusemide.

OBJECTIVE: To study the effect of hyperhydration with normal saline and frusemide on the renal resistive index (RI) in children with equivocal obstructive uropathy. PATIENTS AND METHODS: Twelve children (24 kidneys) with unilateral or bilateral hydronephrosis underwent isotopic diuretic renography and Doppler ultrasonography. All children had equivocal obstruction of the hydronephrotic kidneys with half-time drainage (T/2) values of 10-20 min. Doppler studies were carried out both at baseline and after the infusion of normal saline and frusemide. RESULTS: Of the 24 kidneys, five were normal and 19 were hydronephrotic; compared with normal kidneys, the hydronephrotic units had a significantly lower glomerular filtration rate (GFR) and longer T/2. At baseline, the mean RI values of normal and hydronephrotic kidneys were not significantly different (0.70, SD 0.03 and 0.71, SD 0.04, respectively). After the infusion of saline and frusemide, the mean RI of hydronephrotic kidneys (0.67, SD 0.07) was significantly (P = 0.01) higher than that of normal kidneys (0.60, SD 0.02), but the response of RI in hydronephrotic kidneys was variable. Based on the RI at baseline and after infusion, hydronephrotic kidneys could be categorized into three groups. Group 1 (n = 6) had an RI < 0.7 before and after infusion, group 2 (n = 6) had a baseline RI > 0.7 and < 0.7 after infusion, and in group 3 (n = 7) both RIs were > 0.7. Kidneys in group 3 had the lowest GFR and the highest T/2 values. Five of these seven hydronephrotic kidneys eventually had deteriorating GFRs requiring surgical correction; the GFR of the remaining hydronephrotic kidneys remained stable. CONCLUSION: In children with equivocal obstructive uropathy based on diuretic renography, the determination of RI before and after infusion of normal saline and frusemide could be helpful in distinguishing obstructed from non-obstructed kidneys.

Partial ureteral obstruction: role of renal resistive index in stages of obstruction and release.

OBJECTIVES: To study the changes in renal resistive index (RI) and renal function before and after release of different grades of partial unilateral ureteral obstructions. METHODS: Ten dogs were subjected to right partial ureteral obstruction. Grade 1 (mild) obstruction was applied to 5 dogs (group A) and grade 3 (moderate and severe) obstruction was applied to the other 5 dogs (group B). Obstruction was maintained for 8 weeks, followed by release of obstruction. All dogs were subjected to excretory urography, technetium-99m mercaptoacetyltriglycine diuretic renography with calculation of half-time drainage (T1/2), and bilateral renal Doppler ultrasonography before the start of the experiment, after 8 weeks of obstruction, and every 2 weeks during the 8 weeks after release of obstruction. RESULTS: In both groups, after induction of right ureteral obstruction, there was a dramatic decrease of effective renal plasma flow (ERPF), increase of RI, and increase of T1/2 of the right kidney. Relief of obstruction was associated with normalization of T1/2, reversal of RI, and recovery of ERPF to near basal values. No correlation was found between ERPF at the end of the recovery period and the functional parameters (T1/2, RI, or ERPF) of the obstructed kidney before release of obstruction. CONCLUSIONS: (1) Unilateral partial ureteral obstruction produces an elevation of RI and T1/2 and a fall in ERPF of the corresponding kidney. (2) After relief of function is regained with associated reversal of RI. (3) Functional parameters (T1/2, RI, or ERPF) of the obstructed kidney do not predict the recovery of ERPF after release of obstruction. (4) Rapid reversal of a previously elevated RI is an early indicator of recoverability of renal function after relief of ureteral obstruction.

Emphysematous pyelonephritis: a 15-year experience with 20 cases.

OBJECTIVES: To review our experience with emphysematous pyelonephritis over the past 15 years. METHODS: Twenty patients with emphysematous pyelonephritis were reviewed regarding diagnosis, treatment, and outcome. RESULTS: Women outnumbered men (75% versus 25%), and 80% of patients were diabetic. The left kidney was more frequently affected than the right one (60% versus 35%) and both kidneys were involved in 5%. Obstruction of the corresponding renoureteral unit was found in all the nondiabetic and in half of the diabetic patients. Diagnosis was confirmed by gas in the parenchyma or perinephric space by plain x-ray of the abdomen or computed tomography. Escherichia coli was the most common organism; it was found in 70% of urine cultures. A prompt attempt to control diabetes was made, and intravenous antibiotics were given. Nephrectomy was immediately performed after stabilization of the general condition of the patients. A total of 80% of patients survived the procedures. CONCLUSIONS: For successful management of emphysematous pyelonephritis, appropriate medical treatment should be attempted but immediate nephrectomy should not be delayed.

Partial ureteral obstruction: effect of intravenous normal saline and furosemide upon the renal resistive index.

OBJECTIVE: To investigate the effect of intravenous normal saline fluid load, with and without furosemide, upon the renal resistive index (RI) of obstructed and nonobstructed kidneys. METHODS: Right partial ureteral obstruction was induced in 10 dogs. Grade 1 (mild) obstruction was performed in 5 dogs (group A), and grade 3 (severe) obstruction was carried out to the remaining 5 dogs (group B). Evaluation by Doppler ultrasonography was performed before induction of ureteral obstruction and by the end of the 8th week of obstruction. Every obstructed animal was subjected to bilateral renal Doppler ultrasonography 3 times in one setting: 1) before infusion of normal saline, 2) 30-60 minutes after intravenous infusion of normal saline (15 ml./kg.) given in a rate of 1 ml./kg./min. and 3) 10 minutes after admission of furosemide (1 mg./kg.). RESULTS: After induction of right partial ureteral obstruction, there was a significant increase of the RI of the right kidney and a significant decrease of the RI of the left kidney compared to baseline RI in both groups. Infusion of normal saline and administration of furosemide caused a further significant increase of the RI of the obstructed kidney and a further significant decrease of the RI in the nonobstructed kidney in both groups. CONCLUSION: In unilateral partial ureteral obstruction, addition of intravenous normal saline and furosemide cause the RI to increase in obstructed kidney and to decrease in nonobstructed kidney. Such a divergent response may be useful for the development of a pharmacologically challenged Doppler examination to diagnose better potentially obstructed kidneys.

Partial ureteric obstruction: a study of Doppler ultrasonography and diuretic renography in different grades and durations of obstruction.

OBJECTIVES: To study the changes in renal resistive index (RI) and renal function with time during different grades of partial unilateral ureteric obstruction, and to determine the correlation between the ultrasonographic and renographic findings. MATERIALS AND METHODS: Ten dogs underwent right partial ureteric obstruction: grade 1 (mild) obstruction was applied in five dogs (group A) and grade 3 (moderate and severe) obstruction in the other five (group B). All dogs were assessed using excretory urography, diuretic renography with the calculation of half-time drainage (T 1/2) and bilateral renal Doppler ultrasonography before the experiment began, after one week of obstruction, and every 2 weeks during 8 weeks of obstruction. RESULTS: In both groups, after the induction of right ureteric obstruction, there was a progressive decrease of effective renal plasma flow (ERPF) and a progressive increase of the RI of the right kidney at the end of the first and second weeks of obstruction, with an almost stable value thereafter. The decrease of ERPF and the increase of RI in the right kidney were correlated with the degree of obstruction. There was also a dramatic increase of T 1/2 of the right kidney that correlated with the degree of obstruction. Concomitantly, there was a significant compensatory increase of ERPF and a significant decrease of the RI of the left kidney in both groups. The compensatory increase in CRPF limited the loss in total ERPF in both groups. The contribution of obstructed kidney to the total ERPF was significantly reduced in both groups. At the end of the eighth week, taking all kidneys together, there was a statistically significant negative correlation between the ERPF and RI, and between ERPF and T 1/2 and a positive correlation between T 1/2 and RI. CONCLUSIONS: Unilateral partial ureteric obstruction increased the RI and T 1/2 and decreased the ERPF of the corresponding kidney, together with a decrease of RI and an increase in ERPF of the contralateral kidney. The more severe the obstruction, the greater the increase in RI and T 1/2 and the decrease in ERPF. After the obstruction stabilized, RI and T 1/2 were positively correlated.

Renal Doppler ultrasound in children with obstructive uropathy: effect of intravenous normal saline fluid load and furosemide.

PURPOSE: We studied the effect of hyperhydration with normal saline and furosemide on renal resistive index in children with obstructive uropathy. MATERIALS AND METHODS: 99mTechnetium-mercaptoacetyltriglycine diuretic renography and Doppler ultrasound were done in 27 children (54 renal units) with unilateral or bilateral hydronephrosis. Doppler studies were performed at baseline, and after infusion of normal saline and administration of furosemide. Half-time drainage, considered the gold standard for the diagnosis of renal obstruction, was compared to resistive index. RESULTS: There was a positive correlation between half-time and resistive index on both Doppler studies. With a resistive index of 0.70 as the critical value for predicting renal obstruction 82 versus 100% sensitivity (p < 0.006), 63 versus 94% specificity (p < 0.04) and 76 versus 98% overall accuracy (p < 0.0005) were obtained for Doppler studies at baseline and after induced diuresis, respectively. All children with false-positive results were younger than age 4 years. CONCLUSIONS: Doppler ultrasonography after hyperhydration with normal saline and furosemide is an accurate method for diagnosing renal obstruction in children. It is more sensitive, specific and accurate than baseline Doppler studies.

Doppler ultrasonography in evaluation of potential live kidney donors: a prospective study.

PURPOSE: We compared the accuracy of Doppler ultrasonography and intra-arterial digital subtraction angiography for preoperative visualization of the number of renal arteries in potential live kidney donors. MATERIALS AND METHODS: Intra-arterial digital subtraction angiography and Doppler ultrasonography were used to study the renal anatomy of 64 consecutive kidney donors. Doppler studies were performed without knowledge of the angiographic findings. All donors underwent nephrectomy, and the number of renal arteries at nephrectomy was compared with that predicted by intra-arterial digital subtraction angiography and Doppler ultrasonography. RESULTS: One renal artery was found in 53 harvested kidneys, 2 in 10 and 3 in only 1. Analysis of the data revealed sensitivity 96.2% and specificity 100% for intra-arterial digital subtraction angiography versus sensitivity 100% and specificity 60% for Doppler ultrasound. Overall accuracy was 96.8% for angiography versus 93.7% for Doppler ultrasound, compared to 96.2 and 100%, respectively, for single, and 100% and 60%, respectively, for double renal arteries (p < 0.03). Both tests were interpreted as showing double vessels in the case with triple renal arteries. CONCLUSIONS: Although Doppler ultrasonography is accurate in delineation of single renal arteries, its limited ability to identify multiple arteries should make one cautiously optimistic regarding its current use.

Renal Doppler ultrasound in children with normal upper urinary tracts: effect of fasting, hydration with normal saline, and furosemide administration.

OBJECTIVES: To study the age dependency of renal resistive index (RI) and to study the effect on the renal RI of fasting, intravenous infusion of normal saline, and administration of furosemide in children with normal upper urinary tracts. METHODS: The study included 28 nonobstructed renal units in 15 boys ranging in age from 3 to 11 years. Diuretic renography and Doppler ultrasonography were attempted in all children. Doppler ultrasonography was carried out under three different conditions: fasting state, 30 to 60 minutes after intravenous infusion of normal saline (15 mL/kg), and 10 minutes after administration of furosemide (1 mg/kg; maximum, 40 mg). RESULTS: There was an inverse correlation between age and RI of both renal units under the three conditions of Doppler studies. At fasting state mean RI was 0.70 +/- 0.04, whereas 15 of 28 renal units (54%) had an RI of 0.70 or higher. Intravenous infusion of normal saline significantly decreased the RI to 0.63 +/- 0.04 (P < 0.000001). Injection of furosemide caused a further significant decrease of RI from 0.63 +/- 0.04 to 0.60 +/- 0.04 (P < 0.002). CONCLUSIONS: The renal RI in healthy children is age dependent. In the fasting state, 54% of nonobstructed renal units in children have an RI of 0.70 or higher. Intravenous infusion of normal saline and administration of furosemide can independently cause a significant decrease of the RI in nonobstructed renal units in children.

Destruction of aflatoxins B1 and G 1 in bread making.

The effect of processing steps as well preservatives used in French bread making namely propionic acid and/or potassium sorbate (0.2%) on the destruction of aflatoxins B1 and G1 was studied.Mixing and baking processes showed marked destruction of aflatoxins B1 and G1; being 71.2% and 52.5% for aflatoxin B1 after mixing and baking steps, while reaching 73.9% and 54.5% for aflatoxin G1. Fermentation step caused additional 15.3% and 15.0% destruction of aflatoxins B1 and G1.On the other hand, aflatoxin B1 destruction was 79.2% and 50.7% when propionic acid was used and 75.3 and 56.7% in the presence of potassium sorbate and after mixing and baking steps respectively.Concerning aflatoxins G1 it was found that mixing and baking steps showed destruction of 81.9% and 53.4% in the presence of propionic acid and 75.1 and 49.4% in the presence of potassium sorbate in this respective order.Generally, it can be concluded that using propionic acid as preservative appeared to be more effective on the destruction of aflatoxins B1 and G1 than potassium sorbate in French bread making.

Fate of aflatoxins B1 and G 1 residues during biscuit processing.

Effect of biscuit processing on the destruction of aflatoxins B1 and G1 with and/or without some commonly leavening agents used namely sodium bicarbonate, ammonium bicarbonate and sodium bisulfite and sodium chloride.It was found that mixing step reduced the concentration of aflatoxins B1 and G1 by 80.7% and 82.7%, while the effect of baking step being 28.9% and 21.5%. The effect of mixing was found to be more pronounced than that baking step.The highest destruction effect on aflatoxin B1 was observed by adding a mixture composed of sodium and ammonium bicarbonate and sodium bisulfite followed by sodium chloride, sodium bisulfite, ammonium bicarbonate and/or sodium bicarbonate alone, where the reduction values of toxin after mixing were 93.4,91.9,91.7, 88.8 and 86.6% respectively, while the baking effect ranged 17.2 to 34.5% in the presence of different leaving agents added.Concerning aflatoxin G1; the highest destructive effect of toxin was adsorbed by adding a mixture of sodium and ammonium bicarbonate and sodium bisulfite followed by sodium bisulfite, sodium chloride, ammonium bicarbonate and/or sodium bicarbonate alone since the destruction values of such toxin after mixing were 96.2%, 92.8%, 92.6%, 89.0% and 87.7% respectively, while the baking effect ranged 20.9 to 34.5% in all leavening agents added.

Prostatic abscess in a child.

We report a metastatic prostatic abscess in a 12-year-old boy. Rectal examination revealed a tender, fluctuating prostatic mass, causing acute retention of urine. Prostatic imaging by computerized tomography and transrectal ultrasonography were important in the diagnosis and management.