Histological characterization of venom secretory cells in the stinger of 3 stingrays (Dasyatidae) species: Dasyatis bennetti, Himantura walga, Himantura gerrardi, in northern water of Persian Gulf and Oman Sea

Rays are common elasmobranches in the northern waters of Persian Gulf and Oman Sea that may have one or more mineralized serrated stingers on the whip-like tail. The stingers are covered by epidermal cells among which some can produce venom. When these animals are dorsally touched, the stinger may be introduced into the aggressor by a whip reflex mechanism, causing severe mechanical injuries and inoculating the venom. A comparative morphological characterization of the stinger epidermal tissue of different ray species in the northern part of Persian Gulf and Oman Sea was carried out in this study. EDTA was used for decalcification of stings and conventional histological processes were subsequently employed. The results indicated that structure of dermis and epidermis layers of stings in all species are similar to those of corresponding layers in other parts of fish’s body. The results of the present study have also shown that all three examined species, had venom secretory cells. Distribution of venom secretory cells varies in each species; in Dasyatis bennetti and Himantura walga species, these cells presented in all covered epithelium of stings and in Himantura gerrardi, were in the ventral, ventro-lateral and dorso-lateral of the spine. These differences among the stingers of various species may explain the envenomation severity in these species

Pharmacokinetics of tetracycline hydrochloride after single intravenous injection in dogs

Summary Six mixed-breed apparently healthy dogs were intravenously administered a single dose of tetracycline hydrochloride (50 mg/kg) to evaluate the pharmacokinetic parameters of the drug. Blood samples were collected before and at various time intervals after the administration of the drug. Serum tetracycline concentrations were determined over a 24 h period using fluorescence spectrophotometry. Noncompartmental analysis of the data indicated that tetracycline has a half-life of 4.4 h, a body clearance of around 0.7 ml/kg.min and a volume of distribution of about 0.3 L/kg. The pharmacokinetics of tetracycline found in this study is favourable for therapeutic use in the dog

Derivatives of caffeic acid, a natural antioxidant, as the basis for the discovery of novel nonpeptidic neurotrophic agents

Neurodegenerative disorders, such as Parkinson's disease and Alzheimer's disease, threaten the lives of millions of people and the number of affected patients is constantly growing with the increase of the aging population. Small molecule neurotrophic agents represent promising therapeutics for the pharmacological management of neurodegenerative diseases. In this study, a series of caffeic acid amide analogues with variable alkyl chain lengths, including ACAF3 (C3), ACAF4 (C4), ACAF6 (C6), ACAF8 (C8) and ACAF12 (C12) were synthesized and their neurotrophic activity was examined by different methods in PC12 neuronal cells. We found that all caffeic acid amide derivatives significantly increased survival in PC12 neuronal cells in serum-deprived conditions at 25 μM, as measured by the MTT assay. ACAF4, ACAF6 and ACAF8 at 5 µM also significantly enhanced the effect of nerve growth factor (NGF) in inducing neurite outgrowth, a sign of neuronal differentiation. The neurotrophic effects of amide derivatives did not seem to be mediated by direct activation of tropomyosin receptor kinase A (TrkA) receptor, since K252a, a potent TrkA antagonist, did not block the neuronal survival enhancement effect. Similarly, the active compounds did not activate TrkA as measured by immunoblotting with anti-phosphoTrkA antibody. We also examined the effect of amide derivatives on signaling pathways involved in survival and differentiation by immunoblotting. ACAF4 and ACAF12 induced ERK1/2 phosphorylation in PC12 cells at 5 and 25 µM, while ACAF12 was also able to significantly increase AKT phosphorylation at 5 and 25 µM. Molecular docking studies indicated that compared to the parental compound caffeic acid, ACAF12 exhibited higher binding energy with phosphoinositide 3-kinase (PI3K) as a putative molecular target. Based on Lipinski's rule of five, all of the compounds obeyed three molecular descriptors (HBD, HBA and MM) in drug-likeness test. Taken together, these findings show for the first time that caffeic amides possess strong neurotrophic effects exerted via modulation of ERK1/2 and AKT signaling pathways presumably by activation of PI3K and thus represent promising agents for the discovery of neurotrophic compounds for management of neurodegenerative diseases

Discovery of neurotrophic agents based on hydroxycinnamic acid scaffold

The number of people affected by neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease is rapidly increasing owing to the global increase in life expectancy. Small molecules with neurotrophic effects have great potential for management of these neurological disorders. In this study, different (C1-C12) alkyl ester derivatives of hydroxycinnamic acids (HCAs) were synthesized (a total of 30 compounds). The neurotrophic capacity of the test compounds was examined by measuring promotion of survival in serum-deprived conditions and enhancement of nerve growth factor (NGF)-induced neurite outgrowth in PC12 neuronal cells. p-Coumaric, ferulic, and sinapic acids and their esters did not alter cell survival, while caffeic acid and all its alkyl esters, especially decyl and dodecyl caffeate, significantly promoted neuronal survival at 25 μm. Methyl, ethyl, propyl, and butyl caffeate esters also significantly enhanced NGF-induced neurite outgrowth, among which the most effective ones were propyl and butyl esters, which at 5 μm led to 25- and 22-fold increases in the number of neurites, respectively. The findings of the docking study suggested phosphatidylinositol 3-kinase (PI3K) as the potential molecular target. In conclusion, our findings demonstrate that alkyl esters of caffeic acid can be useful as scaffolds for the discovery of therapeutic agents for neurodegenerative diseases

Berberis vulgaris root extract alleviates the adverse effects of heat stress via modulating hepatic nuclear transcription factors in quails

To evaluate the action mode of Berberis vulgaris root extract in the alleviation of oxidative stress, female Japanese quails (n 180, aged 5 weeks) were reared, either at 22°C for 24 h/d (thermoneutral, TN) or 34°C for 8 h/d (heat stress, HS), and fed one of three diets: diets containing 0, 100 or 200 mg of B. vulgaris root extract per kg for 12 weeks. Exposure to HS depressed feed intake by 8·5 % and egg production by 12·1 %, increased hepatic malondialdehyde (MDA) level by 98·0 % and decreased hepatic superoxide dismutase, catalase and glutathione peroxidase activities by 23·5, 35·4 and 55·7 %, respectively (P< 0·001 for all). There were also aggravations in expressions of hepatic NF-κB and heat-shock protein 70 (HSP70) by 42 and 43 %, respectively and suppressions in expressions of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and haeme-oxygenase 1 (HO-1) by 57 and 61 %, respectively, in heat-stressed quails (P< 0·001 for all). As supplemental B. vulgaris extract increased, there were linear increases in performance parameters, activities of antioxidant enzymes and hepatic Nrf2 and HO-1 expressions (P< 0·001 for all) and linear decreases in hepatic MDA level and NF-κB and HSP70 expressions at a greater extent in quails reared under TN condition and those reared under HS condition. In conclusion, dietary supplementation of B. vulgaris root extract to quails reduces the detrimental effects of oxidative stress and lipid peroxidation resulting from HS via activating the host defence system at the cellular level