Pyrus communis L. (Pear) and Malus domestica Borkh. (apple) leaves lipoidal extracts as sources for beta-sitosterol rich formulae and their wound healing evaluation.

Pyrus communis L. (cv. Le-Conte) (pears) and Malus domestica Borkh. (cv. Anna) (apples) are economic fruit crops cultivated in Egypt. Their leaves were assessed for their beta-sitosterol content and found to have 9.4 mg/g dried leaves wt and 5 mg/g dried leaves, respectively. So we used the lipoidal leaves extracts in the formulation of eight beta-sitosterol-rich emulgels from which the most stable formulae were tested for their antimicrobial activity. Finally, the formulae which exerted antimicrobial activity were biologically evaluated for wound healing against well-known wound healing ointment Mebo® which is composed mainly of 0.25% beta-sitosterol in a base of sesame oil and beeswax. Wound contraction was statistically different in both formulae F3 and F8 from both control and Mebo® groups which indicated better wound healing activity of these formulae ensured by further histopathological study of the healed wounds.

Promising Antidiabetic and Antimicrobial Agents Based on Fused Pyrimidine Derivatives: Molecular Modeling and Biological Evaluation with Histopathological Effect.

Diabetes is the most common metabolic disorder in both developing and non-developing countries, and a well-recognized global health problem. The WHO anticipates an increase in cases from 171 million in 2000 to 366 million by 2030. In the present study, we focus on the preparation of pyrimidine derivatives as potential antidiabetic and antimicrobial agents. Thein vivoeffect on total serum glucose concentration, cholesterol and antioxidant activity was assessed in adult male albino Wister rats and compared to the reference drug glimperide. Promising results were observed for compound 5. The histopathological study confirms that compound 5 results in significant activity with liver maintenance. The antimicrobial activities were evaluated against several bacterial strains such as Salmonella typhimurium ATCC 25566, Bacillus cereus, Escherichia coli NRRN 3008, Pseudomonas aeruginosa ATCC 10145, Staphylococcus aureus ATCC 6538and fungi such as Rhizopus oligosporus, Mucor miehei and Asperillus niger. Compounds 4 and 5 showed a good inhibition of the bacterial zone compared to the reference drug cephradine. Finally, we suggest protein targets for these drugs based on computational analysis, and infer their activities from their predicted modes of binding using molecular modeling. The molecular modeling for compounds 4 and 5 resulted in improved docking scores and hydrogen bonding. The docking studies are in good agreement with the in vitro and in vivo studies.

Mesalazine, an osteopontin inhibitor: The potential prophylactic and remedial roles in induced liver fibrosis in rats.

Liver fibrosis is a major health issue leading to high morbidity and mortality. The potential anti-fibrotic activity and the effect of mesalazine on osteopontin (OPN), an extra cellular matrix (ECM) component were evaluated in TAA-induced liver fibrosis in rats. For this purpose, forty-two adult male Wistar rats were divided into six groups. All animals, except the normal control, were intraperitoneally injected with TAA (200 mg/kg) twice per week for 6 weeks. In the hepato-protective study, animals were administered mesalazine (50 and 100 mg/kg, orally) for 4 weeks before induction of liver fibrosis then concomitantly with TAA injection. In the hepato-therapeutic study, animals were administered mesalazine for 6 weeks after TAA discontinuation with the same doses. In both studies, mesalazine administration improved liver biomarkers through decreasing serum levels of AST, ALT and total bilirubin when compared to fibrotic group with significant increase in total protein and albumin levels. Mesalazine significantly decreased hepatic MDA level and counteracted the depletion of hepatic GSH content and SOD activity. Additionally, it limits the elevation of OPN and TGF-ß1 concentrations and suppressed TNF-α as well as α-SMA levels in hepatic tissue homogenate. Histopathologically, mesalazine as a treatment showed a good restoration of the hepatic parenchymal cells with an obvious decreased intensity and retraction of fibrous proliferation, while as a prophylaxis it didn't achieve enough protection against the harmful effect of TAA, although it decreased the intensity of portal to portal fibrosis and pseudolobulation. Furthermore, mesalazine could suppress the expression of both α-SMA and caspase-3 in immunohistochemical sections. In conclusion, mesalazine could have a potential new indication as anti-fibrotic agent through limiting the oxidative damage and altering TNF-ɑ pathway as an anti-inflammatory drug with down-regulating TGF-ß1, OPN, α-SMA and caspase-3 signaling pathways.

Mice Antibody Response to Conserved Nonadjuvanted Multiple Antigenic Peptides Derived from E1/E2 Regions of Hepatitis C Virus.

Synthetic peptides are one of the hepatitis C virus (HCV)-specific small molecules that have antiviral activity and represent a target for HCV vaccine. This study aims to determine the lowest concentration of adjuvanted and non-adjuvanted (multiple antigenic peptide [MAP]) form of three conserved HCV envelope peptides that can induce murine immunogenic responses and evaluate the neutralization capacities of the generated antibodies (Abs) against HCV in cultured Huh7.5 cells. In this study, three HCV synthetic peptides, E1 peptide (a.a 315-323) and E2 peptides (a.a 412-419 and a.a 516-531) were synthesized. Female Balb/c mice were immunized with different concentration of either adjuvanted linear peptides or nonadjuvanted MAP peptides to determine the lowest dose that generates Ab responses enough to confer viral neutralization in vitro. The humoral responses targeting these peptides in immunized mice sera were measured by enzyme-linked immunosorbent assay (ELISA). Viral neutralization capacities of the generated mice Abs were assessed using Huh7.5 cells infected with the HCVcc infectious system (J6/JFH-1). The results of this study showed that the MAPs induce higher Ab titers than adjuvanted linear peptides after 4 weeks of immunization (p = 0.003). The viral neutralization experiments showed that the immunized mice sera contain anti E1/E2 Abs that blocked HCVcc (J6/JFH-1) entry into Huh7.5 cells. In conclusion, the three HCV envelope MAP peptides are more immunogenic and produce higher neutralizing Abs than linear peptides; therefore, they can be essential components for HCV vaccine.

Resveratrol prevents liver fibrosis via two possible pathways: Modulation of alpha fetoprotein transcriptional levels and normalization of protein kinase C responses.

OBJECTIVE: Liver fibrosis is a global health problem that causes approximately 1.4 million deaths per year. It is associated with inflammation, oxidative stress, necrosis and ends with cirrhosis, liver cancer, or liver failure. Therefore, the present study was constructed to investigate the protective effect of resveratrol (RVT) on liver fibrosis, focusing on the possible involvement of alpha 1-fetoprotein and protein kinase C signaling. MATERIALS AND METHODS: Rats received thioacetamide (TAA) (200 mg/kg, intraperitoneal) twice weekly, for 4 successive weeks to induce liver fibrosis. RVT (30 mg/kg, per os) and vehicle were administered orally for 1 month before and another month during TAA intoxication. Body weights and mortality rate were assessed during the experiment. Liver functions and protein concentration were determined in serum, while liver tissues were analyzed for oxidative and fibrotic biomarkers. Moreover, histological examinations were performed to liver biopsies. RESULTS: RVT prevented the debility of TAA; liver functions including alanine aminotransferase, aspartate aminotransferase, bilirubin, and albumin were also protected. RVT prevented TAA oxidative stress, and normal liver contents of malondialdehyde and reduced glutathione were markedly preserved. In addition, RVT abolished the stimulant effect of TAA to fibrosis markers and conserved normal liver contents of nuclear factor kappa B, hydroxyproline, and alpha fetoprotein. Histological examinations indicated normal liver architecture in RVT-administered rats as compared to their TAA-administered peers. CONCLUSION: RVT was able to enhance liver functions, prevent oxidative stress, and eliminate liver fibrosis. Hence, the present data highlight the therapeutic potential of RVT as a protective agent against liver fibrosis.

Effect of a topical copper indomethacin gel on inflammatory parameters in a rat model of osteoarthritis.

OBJECTIVE: We aimed to investigate the effect of topical application of a Copper indomethacin (Cu-Indo) gel preparation on monosodium iodoacetate (MIA) induced arthritis of the knee joint of rats and to test our hypothesis that copper complex of indomethacin could be a more potent anti-inflammatory agent than its parent compound. METHODS: After induction of osteoarthritis by the intracapsular injection of 50 µL with 40 mg/mL MIA, we compared the anti-inflammatory efficacy and safety of a topical application of 1% indomethacin gel in a dose of 1 g/kg of the gel (equivalent to 10 mg/kg of the active substance) daily for 3 weeks versus three decremental dose levels of Cu-Indo gel: an equivalent dose, half the dose, and 25% of the dose of indomethacin. Anti-inflammatory efficacy was assessed in all treated groups by measurement of serum inflammatory cytokines: interleukin 6, interleukin 8, and tumor necrosis factor alpha; and by the weekly assessment of knee joint swelling. Joint mobility and motor coordination were also assessed once weekly by the accelerating rotarod apparatus; histopathological examination of affected joints was also performed. Safety of topical application of Cu-Indo (0.25, 0.5, and 1 g/kg) for up to 3 months to rats' skin was determined by the estimation of a complete blood count, liver and kidney functions, and histopathologic examination for target tissues. RESULTS: Cu-Indo gel at lower doses was superior to or at least as effective as its parent substance, indomethacin, in most of the studied parameters of inflammation. The lowest tested dose of Cu-Indo, corresponding to 25% of the parent substance indomethacin, exhibited the highest efficacy in reducing the elevated serum-tested interleukins and in increasing the time of duration on the rotarod test, whereas its effect on reduction of edema and tumor necrosis factor alpha was comparable to that of the others. After 3 months of daily application, there were no notable changes in studied safety parameters with the lowest Cu-Indo dose, but the group treated with the higher dose showed a small but statistically significant increase in serum-unconjugated bilirubin and a slight decrease in hemoglobin levels, red blood cells, and platelet count, with normal indices denoting a slight hemolytic effect at the highest dose. CONCLUSION: Cu-Indo gel has potent anti-inflammatory activity against joint inflammation in the MIA-treated rat model of osteoarthritis at doses of 0.25, 0.5, and 1 g/kg. The lowest studied dose was better on both safety and efficacy parameters.

Lactoferrin Enhanced Apoptosis and Protected Against Thioacetamide-Induced Liver Fibrosis in Rats.

BACKGROUND: Liver fibrosis is the common pathologic consequence of all chronic liver diseases. AIM: Lactoferrin (Lf) was investigated for its possible hepatoprotective effect against thioacetamide (TAA)-induced liver fibrosis rat model. MATERIAL AND METHODS: Rats received TAA (200 mg/kg/biweekly, ip) for four successive weeks. Lf (200 mg/kg/day, p.o.) or vehicle (VHC) was administered for one month before and another month during TAA injection. Body weight and mortality rate were assessed during the month of TAA-intoxication. Thereafter, serum and liver tissues were analyzed for liver function, oxidative, fibrotic and apoptotic markers. RESULTS: Lf conserved rats against TAA-induced body weight-loss and mortality. Preservation of serum albumin, alkaline phosphatase and total bilirubin levels was also observed. Lf also protected rats against TAA-induced decrease in reduced glutathione and increase in malondialdehyde liver contents. Normal liver contents of hydroxyproline, nuclear factor kappa B and alpha fetoprotein; as markers of fibrosis; were increased with TAA and conserved with Lf-TAA. Lf maintained the normal architecture of the liver and immunohistochemical findings revealed increase in apoptotic bodies compared to TAA that favored necrosis. CONCLUSION: In conclusion, Lf improved liver function, reduced oxidative stress and liver fibrosis, and enhanced apoptosis in rats with liver fibrosis, suggesting it to have useful therapeutic potential in patients with liver fibrosis.

Comparative DNA profiling, phytochemical investigation, and biological evaluation of two Ficus species growing in Egypt.

AIM AND BACKGROUND: A comparison between two Ficus species, cultivated in Egypt, was carried out in this study. Their DNA analysis revealed that they are not closely related. MATERIALS AND METHODS: The pharmacopoeial constants of the leaves showed higher total ash and acid insoluble ash in F. lyrata than in F. platypoda. The other parameters were close in both species. Preliminary phytochemical screening revealed the presence of carbohydrate and/or glycosides, tannins, flavonoids, sterols, and triterpenes in their leaves and was detected in traces in their stems. RESULTS: Saponification of n-hexane extract of the leaves yielded 46% and 74.8% for the unsaponifiable matters and 20% and 15% for the fatty acids for F. platypoda and F. lyrata, respectively. n-Docosane (21.69%) and n-heptacosane (33.77%) were the major hydrocarbons in F. platypoda and F. lyrata, respectively. b-Sitosterol was the main sterol, palmitic (22.07%) and carboceric (35.72%) acids were the major identified saturated fatty acids in both species, while linoleic acid was the main unsaturated fatty acid (18.66% and 16.7%) in both species, respectively. The acute toxicity study revealed that the two species were safe up to 2 g/kg. The antioxidant activity using 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay and pyrogallol as the standard was more significant for F. platypoda (232.6 µg/ml) than for F. lyrata, (790.9 µg/ml). The oral antihyperglycemic activity in diabetic rats using alloxan revealed that the 80% ethanolic extract of the leaves of F. platypoda was more active than that of the leaves of F. lyrata in decreasing the blood glucose level at 200 mg/kg/day (107.9 ± 5.817, 127.2 ± 4.359) and 400 mg/kg/day (64.11 ± 4.358, 127.7 ± 6.889), respectively, when compared with the diabetic control gliclazide (172.3 ± 2.089). CONCLUSION: The results of this study provide evidence that the two Ficus species have antioxidant and antihyperglycemic activity, in the order F. platypoda and then F. lyrata.

Tissue distribution and efficacy of gold nanorods coupled with laser induced photoplasmonic therapy in ehrlich carcinoma solid tumor model.

Gold nanorods (GNR) within tumor microregions are characterized by their ability to absorb near IR light and emit heat in what is called photoplasmonic effect. Yet, the efficacy of nanoparticles is limited due to intratumoral tissue distribution reasons. In addition, distribution of GNRs to normal tissue might result in non specific toxicity. In the current study, we are assessing the intratumoral and tissue distribution of PEGylated GNRs on the top of its antitumor characteristics when given intravenously or intratumoral to solid tumor bearing mice and coupled with laser photoplasmonic sessions. PEGylated GNRs with a longitudinal size of less than 100 nm were prepared with aspect ratio of 4.6 showing strong surface plasmon absorption at wavelength 800 nm. Pharmacokinetics of GNR after single I.V. administration (0.1 mg/kg) showed very short systemic circulating time (less than 3 h). On the other hand, tissue distribution of I.V. GNR (0.1 mg/kg) to normal animals showed preferential deposition in spleen tissue. Repeated administration of I.V. GNR resulted in preferential accumulation in both liver and spleen tissues. In addition, I.V. administration of GNR to Ehrlich carcinoma tumor bearing mice resulted in similar tissue distribution; tumor accumulation and anti-tumor effect compared to intratumoral administration. In conclusion, the concentration of GNR achieved within tumors microregions after I.V. administration was comparable to I.T. administration and sufficient to elicit tumoral growth arrest when coupled with laser-aided photoplasmonic treatment.

Effects of pentoxifylline, 7-nitroindazole, and imipramine on tumor necrosis factor-α and indoleamine 2,3-dioxygenase enzyme activity in the hippocampus and frontal cortex of chronic mild-stress-exposed rats.

OBJECTIVES: This study aimed to investigate the role of tumor necrosis factor (TNF)-α and the neuronal nitric oxide synthase enzyme in dysregulation of indoleamine 2,3-dioxygenase (IDO) enzyme, and hence serotonin availability in chronic mild stress (CMS), an animal model of depression. METHODS: RATS WERE DIVIDED INTO FIVE GROUPS: two control and CMS-exposed for 6 weeks, and another three groups exposed to CMS and administered pentoxifylline 50 mg/kg/day intraperitoneally, 7-nitroindazole 40 mg/kg/day subcutaneously, or imipramine 20 mg/kg/day intraperitoneally for the previous 3 CMS weeks. Rats were assessed for neurochemical and immunohistochemical abnormalities. RESULTS: Pentoxifylline-, 7-nitroindazole-, and imipramine-treated rats showed amelioration of CMS-induced behavioral deficits that was accompanied by significant reduction in kynurenine/serotonin molar ratio and nitrates/nitrites in frontal cortex and hippocampus. In the pentoxifylline and 7-nitroindazole groups, serum TNF-α was reduced relative to the CMS group (18.54 ± 0.85 and 19.16 ± 1.54 vs 26.20 ± 1.83 pg/mL, respectively; P < 0.05). Exposure to CMS increased TNF-α and IDO immunohistochemical staining scores in both hippocampus and midbrain raphe nuclei. 7-Nitroindazole and pentoxifylline significantly (P < 0.05) reduced TNF-α immunostaining in hippocampus and raphe nuclei, with significant (P < 0.01) reduction of IDO immunostaining in raphe nuclei. Likewise, imipramine reduced TNF-α immunostaining (P < 0.05) in hippocampus. CONCLUSION: Neuronal nitric oxide synthase and TNF-α may play a concerted role in modulating IDO enzyme activity in CMS-exposed rats and provide additional evidence for possible alternative approaches to switch the neurobiological processes in depression.

Antihypercholesterolaemic effect of ginger rhizome (Zingiber officinale) in rats.

INTRODUCTION: Many herbal medicinal products have potential hypocholesterolaemic activity and encouraging safety profiles. However, only a limited amount of clinical research exists to support their efficacy. AIM OF THE WORK: The present study was designed to evaluate the antihypercholesterolaemic effects of aqueous ginger (Zingiber officinale) infusion in hypercholesterolaemic rat models. METHODS: 48 rats were used throughout the experiment, which were divided into six groups, eight animals each as follows: normal control group (normal rats which fed with standard diet). After induction of hypercholesterolaemia by feeding rats with high cholesterol diet, the remaining rats were divided into five groups: group 1, hypercholesterolaemic control group (hypercholesterolaemic rats group); groups 2, 3 and 4, rats were given aqueous infusion of ginger (100, 200 and 400 mg/kg, respectively) orally; and group 5, rats were given atorvastatin (0.18 mg/kg) orally as a reference antihypercholesterolaemic drug. The blood was obtained from all groups of rats after being lightly anaesthetized with ether and the following lipid profile [serum total cholesterol (TC), HDL-cholesterol (HDL-C), LDL-C and triglyceride levels] was measured at zero time and 2 and 4 weeks after ginger and atorvastatin treatment, and the risk ratio (TC/HDL-cholesterol) was assessed. RESULTS: The results revealed that the hypercholesterolaemic rats treated with aqueous ginger infusion in the three doses used after 2 and 4 weeks of treatment induce significant decrease in all lipid profile parameters which were measured and improved the risk ratio.