Prenatal exposure to ethion caused maternal and foetal toxicity in rats.

Ethion is a class II moderately toxic organothiophosphate pesticide. The main objective of this study was to evaluate the maternal and foetal toxicity of ethion in rats. Pregnant rats were divided into 5 groups. Group I served as control. Group II, III, IV, and V were orally administered with 0.86, 1.71, 3.43, and 6.9 mg/kg of ethion respectively, from gestational day (GD) 6-19. Dams were sacrificed on GD 20. Maternal toxicity was assessed by body weight gain, foetal resorptions, oxidative stress, liver and kidney function tests, and histopathology. Foetal toxicity was assessed by physical status, gross, teratological and histopathological examination. Ethion caused dose-dependent reduction in maternal body weight gain, increased resorptions, and reduced gravid uterine weights. Elevated MDA levels and altered levels of GSH, SOD and catalase were recorded in pregnant dam serum and tissues. SGOT, SGPT, total bilirubin, urea, uric acid, and creatinine were elevated in ethion groups indicating liver and kidney toxicity. Histology of uterus revealed myometrial degeneration and mucosal gland atrophy in uterus of pregnant dams and degenerative changes in placenta. It showed histological alterations in liver, kidney, and lungs. There was reduction in the foetal body weights and placental weights, and degenerative changes in the foetal liver and kidney. Gross evaluation of foetuses showed subcutaneous hematoma. Skeletal evaluation showed partial ossification of skull bones, costal separation, and agenesis of tail vertebrae, sternebrae, metacarpals and metatarsals. The findings reveal that prenatal exposure to ethion caused maternal and foetal toxicity in rats.

PRE-084 ameliorates adenine-induced renal fibrosis in rats.

2-(4-morpholinoethyl)- 1-phenylcyclohexane-1-carboxylate hydrochloride (PRE-084) is a selective sigma 1 receptor agonist. It has been shown that PRE-084 protected various tissues from experimental injury. However, no reports are available on its effect on renal fibrosis. Rat model of adenine-induced chronic kidney disease was chosen to study this. Adenine feeding in rats caused renal dysfunction as shown by increased serum creatinine and reduced creatinine clearance along with increased high molecular weight (HMW) urine protein excretion. Further, adenine feeding induced profibrotic changes in the kidney as reflected by increased expression of alpha-smooth muscle actin (α-SMA), fibroblast specific protein-1 (FSP-1) and matrix metalloproteinase-2 (MMP-2) activity; reduced cytokeratin expression. Further, there was excess deposition of extracellular matrix in the kidney, a striking character of fibrosis. However, administration of PRE-084 to adenine fed rats led to reduction in creatinine and proteinuria parameters partly. This was accompanied by reduced expression of α-SMA, FSP-1 and MMP-2 activity and slight restoration of cytokeratin levels leading to reduced extracellular matrix deposition in the kidney. These data demonstrate that PRE-084 partly ameliorated renal dysfunction and exhibited anti-fibrotic potential in the kidney of adenine fed rats.

Topical bilirubin-deferoxamine hastens excisional wound healing by modulating inflammation, oxidative stress, angiogenesis, and collagen deposition in diabetic rats.

AIM OF THE STUDY: The study was performed to understand the detailed mechanism of diabetic wound healing by bilirubin-deferoxamine (DFO) combination on topical application. MATERIALS AND METHODS: There were two study groups, control, and treatment. The granulation tissues collected on different days (3, 7, 14, and 19) were studied in detail for inflammatory mediators, angiogenesis markers, epithelialization, and oxidative stress parameters. RESULTS: A significant increase in wound contraction percentage was observed from day 7 in the bilirubin-DFO treatment group. The combinatorial treatment significantly reduced tumour necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1ß), and enhanced IL-10 levels. Upregulated mRNAs of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 alpha (HIF-1 α) along with CD31 immunohistochemistry showed the pro-angiogenesis potential of the combination. Hematoxylin and Eosin (H and E) staining and Masson's trichrome staining showed reduced inflammatory cell infiltration, enhanced fibroblast proliferation, well-organized collagen fibers, and the development of new blood vessels. Collagen deposition is further supported by immunohistochemistry studies and Masson's trichrome staining. Bilirubin-DFO combination also reduced lipid peroxidation and elevated antioxidative enzymes. CONCLUSION: Topical application of bilirubin-DFO showed immense potential in augmenting skin wound regeneration in diabetes by upregulating the antioxidant status as well as increasing angiogenesis, collagen deposition, and modulating cytokines.

Differential Expression of Prostaglandin Receptors in Canine Uterus With Pyometra.

The objective of the study was to ascertain the role of prostaglandins Viz., PGE2 and PGF2α, and their respective receptors in the pathophysiology of canine pyometra. Normal (n = 6) and pyometra (n = 8) affected uterus were collected from bitches undergoing ovariohysterectomy. Pyometra was graded according to histopathological alterations. The levels of PGE2 and PGF2α were estimated in the endometrium. The differential expression in the mRNA of PGF2α receptor (FP) and PGE2 receptors (EP1, EP2, EP3, and EP4) were studied in the endometrium and myometrium of the pyometra-affected uterus. Normal uterus served as calibrator. Elevation of both PGE2 and PGF2α levels in the endometrium of pyometra-affected bitches was observed. The FP receptor gene in the endometrium and myometrium of pyometra-affected bitches was downregulated (P < .05). Out of all EP receptors, only EP2 receptor has shown upregulation in both endometrium and myometrium of pyometra affected uterus. EP3 receptor got downregulated in both endometrium and myometrium in pyometra. Thus, downregulation of FP, EP3 receptors in the myometrium reinforces the lack of contractility in pyometra-affected bitches favoring bacterial proliferation and subsequent pus accumulation. Moreover, upregulation of EP2 receptors in the pyometra bitches suggests the scope of selective pharmacological inhibition of EP2 receptors as an adjunct therapy in the treatment of pyometra.

Histamine receptors mediate contraction of reticular groove smooth muscle of adult goats.

The present study was conducted to evaluate the effect of histamine and to characterise its receptor subtypes in reticular groove (RG) smooth muscle of adult goats. The studies were done using floor and lip regions of RG. We used tension experiments on smooth muscle of RG isolated from adult goat for functional characterisation of H1 and H2 receptors. Western blotting and immunohistochemistry experiments were conducted for molecular characterisation of these receptors. Histamine evoked concentration-dependent contraction of isolated RG circular and longitudinal smooth muscle preparation. Pyrilamine antagonised the action of histamine. Histamine did not induce any relaxant effect on RG preparations. Additionally, cimetidine did not produce any significant effect on histamine-induced response. Non-selective histaminic receptor antagonist cyproheptadine attenuated the contraction response to histamine in the smooth muscle. Molecular characterisation and localisation of H1 and H2 receptor proteins confirmed the presence of these receptors in RG. It is most likely that histamine-induced contractile effect in RG smooth muscle of goats is mediated by H1 histaminic receptors.

Current therapeutic applications and pharmacokinetic modulations of ivermectin.

Ivermectin is considered to be a wonder drug due to its broad-spectrum antiparasitic activity against both ectoparasites and endoparasites (under class of endectocide) and has multiple applications in both veterinary and human medicine. In particular, ivermectin is commonly used in the treatment of different kinds of infections and infestations. By altering the vehicles used in the formulations, the pharmacokinetic properties of different ivermectin preparations can be altered. Since its development, various vehicles have been evaluated to assess the efficacy, safety, and therapeutic systemic concentrations of ivermectin in different species. A subcutaneous route of administration is preferred over a topical or an oral route for ivermectin due to superior bioavailability. Different formulations of ivermectin have been developed over the years, such as stabilized aqueous formulations, osmotic pumps, controlled release capsules, silicone carriers, zein microspheres, biodegradable microparticulate drug delivery systems, lipid nanocapsules, solid lipid nanoparticles, sustained-release ivermectin varnish, sustained-release ivermectin-loaded solid dispersion suspension, and biodegradable subcutaneous implants. However, several reports of ivermectin resistance have been identified in different parts of the world over the past few years. Continuous use of suboptimal formulations or sub-therapeutic plasma concentrations may predispose an individual to resistance toward ivermectin. The current research trend is focused toward the need for developing ivermectin formulations that are stable, effective, and safe and that reduce the number of doses required for complete clinical cure in different parasitic diseases. Therefore, single-dose long-acting preparations of ivermectin that provide effective therapeutic drug concentrations need to be developed and commercialized, which may revolutionize drug therapy and prophylaxis against various parasitic diseases in the near future. The present review highlights the current advances in pharmacokinetic modulation of ivermectin formulations and their potent therapeutic applications, issues related to emergence of ivermectin resistance, and future trends of ivermectin usage.

Lecithin-based deferoxamine nanoparticles accelerated cutaneous wound healing in diabetic rats.

Nanoparticles have higher frequency of being exposed to cells or tissue, and are thus more likely to gain access into cytoplasm or nuclei to modulate molecular events due to significantly larger surface area to volume ratio. As a result, they present amplified response or even different physiochemical and biomedical properties from bigger particles. Deferoxamine accelerates wound healing in diabetic rats by increased neovascularization, reduced inflammation and improved maturation of wound. We investigated the wound healing potential of deferoxamine-nanoparticles in diabetic rats. Lecithin based nanoparticles of deferoxamine were prepared and characterized. The diabetic rats were divided into five Groups, of which Group I was treated with pluronic-gel f-127 (25%), Group II with deferoxamine 0.1% and Group III, IV and V were treated with deferoxamine-nanoparticles incorporated in pluronic-gel f-127 25% at 0.03% (0.01% deferoxamine), 0.1% (0.03% deferoxamine) and 0.3% (0.1% deferoxamine) w/v respectively. The wound closure was significantly accelerated in group V as compared to control groups. HIF-1α, VEGF, SDF-1α, TGF-ß1, and IL-10 protein levels were significantly higher in group V. The collagen deposition and neovascularization was greater in deferoxamine-nanoparticle treated rats. In contrast, TNF-α level was lowest in group V. In summary, the deferoxamine-nanoparticle formulation we developed, when applied topically on diabetic wounds results in faster wound healing as compared to simple deferoxamine formulation. This formulation may prove to be an effective therapy for treatment of diabetic wounds.