Combinatorial antitumor effect of naringenin and curcumin elicit angioinhibitory activities in vivo.

Curcumin has long been used as an antioxidative, antiinflammatory, and modulator of pathological angiogenesis, whereas naringenin is a well-known immunomodulator. In this report, we investigated the effect of curcumin and naringenin on the growth of Ehrlich ascites carcinoma tumor model. To achieve this, Swiss albino mice were implanted intraperitoneally with 1 × 106 Ehrlich ascites carcinoma cells followed by the administration of oral doses of naringenin and curcumin either individually (50 mg/kg body weight) or in combination (20 mg/kg body weight each). A marked reduction has been seen in the total number of cells (80%) and accumulation of ascetic fluid (55%) when these drugs were administered together. These drugs proved to be an effective angio-inhibitory compound and confirmed by different in vivo assay systems, viz. peritoneal/skin angiogenesis and chorioallantoic membrane assay. Antiangiogenic and antiproliferative effect of these compounds alone or in combination was further corroborated with immunoblot results where we confirmed the downregulation of vascular endothelial growth factor, Hif1α, heat shock protein 90, and p-Akt. Furthermore, treatment with naringenin and curcumin alone or in combination substantially improved hepatocellular architecture and no noticeable neoplastic lesions or cellular alteration were reported. These outcomes put forward a plausible clinical application of these diet-derived compounds, as both angioinhibitory and antitumor in association with conventional therapy.

Enzymatic detergent in rat peritoneum. A comparative study with physiological solution.

BACKGROUND: Peritoneal washing out with physiological solution with different substances added is useful in peritoneal infections, but the effect of enzymatic detergents, such as quaternary didecyl-dimethyl ammonium compounds (DDAC), used in the sterilization of surgical material is unknown. We undertook this study to determine histological changes (inflammation, fibrosis and new vessel formation) in the peritoneum of Wistar rats after the application of physiological solution or DDAC. METHODS: The minimum inhibitory concentration (MIC) of DDAC for E. coli (512 µg/ml) and E. faecalis (128 µg/ml) was determined. Sixty-three Wistar rats weighing 200 ± 20 g were studied. They were divided into three groups: control: 7 rats were instilled with 3 ml of physiological solution in peritoneal cavity; groups 1 and 2 were instilled with 3 ml of MIC for E. coli and E. faecalis, respectively. These groups were divided into four subgroups of seven animals. In every rat, 1 cm(2) of peritoneum was obtained at 2, 7, 14, and 21 days for histological study with hematoxylin-eosin. Ten fields were evaluated. The data obtained were analyzed with the Mann-Whitney test. RESULTS: There were no significant differences in inflammation, fibrosis and new vessel formation with the physiological solution vs. DDAC at 2, 7, 14, and 21 days (p >0.05), except for inflammation at 2 days in group 2 (p = 0.026), which remitted. CONCLUSIONS: There was no significant difference in changes in rat peritoneum after physiological solution or DDAC application.

Topical and systemic anti-inflammatory effects of Echinodorus macrophyllus (Kunth) Micheli (Alismataceae).

Echinodorus macrophyllus leaf has been used in Brazilian folk medicine to treat inflammatory conditions and kidney dysfunctions. The present study evaluated the effects of leaf ethanolic extract from E. macrophyllus (EEEm) in acute and subchronic models of inflammation. The EEEm was found to cause significant and potent inhibition of carrageenan- and dextran-induced paw edema in rats and marked decreases in the exudate volume and leukocyte migration in rats with carrageenan-induced pleurisy, the vascular permeability increase induced by intraperitoneal acetic acid, and the croton oil-induced topical ear edema in mice. On the other hand, the EEEm was not active in the test model of cotton pellet-induced granuloma in rats. Phytochemical analysis with E. macrophyllus leaves revealed the presence of triterpenoids, steroids, flavones, flavonols, and xanthones. Two flavonoids were isolated from the ethyl acetate fraction and identified as isovitexin and vitexin. Our results support the traditional use of E. macrophyllus leaves in the treatment of acute inflammatory conditions.

Primo-vessels as new flow paths for intratesticular injected dye in rats.

After intratesticular injection of a chromium hematoxylin and fluorescent nanoparticle solution, we found a novel flow path in the abdominal cavity consisting of primo-vessels and primo-nodes. This flow path formed a network that crossed over the surfaces of abdominal organs, and generally linked to the greater omentum and adjacent visceral peritoneum. Some of these structures terminated at organs such as the small intestine and the urinary bladder; occasionally, the network entered the parenchyma of organs. The semitransparent primo-vessels and nodes were wholly or partially stained dark-blue by chromium hematoxylin. Injected nanoparticles were also observed in primo-vessels and nodes as well as the parenchyma of organs which were the site of primo-vessel termination. Transmission electron microscopy showed that the primo-vessels consist of many sinuses (4-6 mum), surrounded by collagen fibers, specific granules, cellular remnants, immune cells, extracellular matrices, and hematopoietic cells. These histological features are completely different from blood and lymph vessels indicating that primo-vessels are novel structures that allow the flow of dye.

Catheter patency and peritoneal morphology and function in a rat model of citrate-buffered peritoneal dialysis.

BACKGROUND: Single-dwell studies in rats and humans have shown that supplementing citrate for lactate in peritoneal dialysis (PD) fluids improves ultrafiltration (UF). ♢ METHODS: The long-term effects of citrate-substituted PD fluids on PD catheter patency, UF, and peritoneal morphology were evaluated in a rat model over 5 weeks of daily PD fluid exposure. A standard 2.5% glucose 40 mmol/L lactate PD fluid and a corresponding 10/30 mmol/L citrate/lactate PD fluid were compared. In a control group, rats with catheters received no PD fluid. ♢ RESULTS: The average patency time (% of 36 days) of silicone rubber PD catheters was significantly longer in the citrate PD group (98.8% ± 1.2%) and the control group (100% ± 0%) compared to the lactate PD group (54.7% ± 9.5%). In a separate experiment, heparin-coated polyurethane catheters were used to study peritoneal morphology and fluid transport. The citrate group had a higher net UF than the lactate group at the beginning and at the end of the 5 weeks. During the experiment, both fluid-treated groups suffered from UF loss; the control group showed the highest net UF at the end of the 5 weeks. Peritoneal vascular density and submesothelial thickness, indicators of angiogenesis and fibrosis, were not significantly different among the groups. Fibrosis was significantly negatively correlated to osmotic UF. ♢ CONCLUSION: A positive acute effect of citrate on UF was confirmed and conserved over time. Citrate PD strongly improved PD catheter patency time compared with lactate. Both citrate PD and lactate PD induced negative long-term effects on UF compared with control animals.

Pre-clinical study of the epinephrine-cisplatin association for the treatment of intraperitoneal carcinomatosis.

We have previously shown that intraperitoneal (i.p.) epinephrine enhances tumour penetration and anti-cancer activity of i.p.-administered cisplatin in rats with peritoneal carcinomatosis. Here, we show a direct correlation between the i.p. epinephrine concentration and cisplatin accumulation in rat peritoneal tumour nodules up to a concentration of 5 mg/l. This concentration leads to a maximal 3.7-fold increase of tumour platinum content and a maximal vasoconstriction of the peritoneal and tumour superficial microcirculation when registered by a laser doppler probe. Further, epinephrine half-life was 20.8+/-3.6 min in the peritoneal cavity of two laparotomized pigs. In these animals, epinephrine plasma concentration, heart rate and systolic blood pressure were dependent on the intraperitoneal dose of epinephrine, and life-threatening signs were not observed in either animal. In conclusion, a 5 mg/l concentration of epinephrine could be safely maintained in peritoneal fluid by regular replacement. This concentration is sufficient to maintain a constant vasoconstriction of the peritoneal and tumoral microvascular bed, and enhance the slow diffusion of cisplatin into peritoneal tumour nodules in the course of per-operative intraperitoneal chemotherapy.

Effects of vasodilators on peritoneal solute and fluid transport in rat peritoneal dialysis.

The pharmacological manipulation by vasodilators of peritoneal solutes and fluid kinetics was investigated. Rats were dialyzed for 240 minutes with 30 mL 4.25% glucose dialysate containing dextran 70. An angiotensin-converting enzyme inhibitor (captopril), three calcium channel blockers (nicardipine, diltiazem, and verapamil), and an +/-blocker (maxisylite) were administered intraperitoneally at various concentrations. Membrane permeability to urea, glucose, and protein, actual net ultrafiltration rate (UFR), transcapillary ultrafiltration rate (TCUFR), and peritoneal net fluid absorption rate (PNFAR) were measured. All three vasodilators caused a decrease in blood pressure, which, except for moxisylite, was associated with a decrease in net UFR. Captopril and the three calcium antagonists increased PNFAR dose dependently. Captopril increased membrane permeability to small and large molecular solutes, with a consequent decrease in TCUFR. Nicardipine and verapamil increased permeability to urea and glucose but not to protein. Only the latter decreased TCUFR. Diltiazem caused no change in permeability. In conclusion, various vasodilators administered intraperitoneally affect peritoneal solute and fluid transport differently. This should, perhaps, be taken into consideration when working with continuous ambulatory peritoneal dialysis (CAPD) patients to whom antihypertensive drugs are administered in large doses.

Selective inhibition by magnosalin and magnoshinin, compounds from 'shin-i' (Flos magnoliae), of adjuvant-induced angiogenesis and granuloma formation in the mouse pouch.

Inhibitory effects of magnosalin and magnoshinin, compounds from the crude drug 'Shin-i' (Flos magnoliae), on angiogenesis and pouch granuloma formation induced by an adjuvant containing croton oil were investigated. Magnosalin inhibited angiogenesis 2.4-fold (intra-pouch) and 9.7-fold (intraperitoneal) more strongly than granuloma formation. The inhibition of angiogenesis by magnosalin was 5-fold (intra-pouch) and 21-fold (intraperitoneal) weaker than that by hydrocortisone. In contrast, intraperitoneal magnoshinin inhibited granuloma formation 2.5-fold more strongly than angiogenesis. The regression coefficients of anti-angiogenesis vs. the inhibition of granuloma formation were 1.79 for magnosalin, 1.11 for hydrocortisone, and 0.61 for magnoshinin. These results show that the anti-chronic inflammatory effect of 'Shin-i' was caused by selective inhibition of angiogenesis by magnosalin and of granuloma formation by magnoshinin.