Immunopathological effects of experimental T-2 mycotoxicosis in Wistar rats.

It is well known that T-2 toxin has cytotoxic radiomimetic like effects on the immune system. Because of scant research data demonstrating the chronic effects of low doses of the T-2 toxin on humoral and cellular responses in rats, the present experiment was undertaken. The animals were divided into four groups, namely, group I (0.5 ppm), group II (0.75 ppm) and group III (1.0 ppm) and group IV (control) were given toxin-free diet for 12 weeks and eight animals each were sacrificed at 2, 4, 6, 8, 10, and 12-week of the experimental period. The humoral immune response was evaluated based on hemagglutination test (HA), and levels of serum immunoglobulins (IgA, IgG, IgM) while the cell-mediated immune response was evaluated by delayed-type hypersensitivity (DTH) response to ovalbumin, lymphocyte stimulation index, analyses of CD4+ and CD8+ T lymphocytes and mRNA expression levels of selected cytokines like IL-2, IFN-γ, IL-4 and IL-10 by quantitative Real-time PCR in experimental groups. T-2 treatment caused suppression in both humoral and cell-mediated immune responses as evidenced by a decrease in all these parameters in toxin fed animals compared to the control in the dose and duration-dependent manner. This dose-dependent effect on the immune system has been further reflected largely by the depletion of lymphocytes from lymphoid organs as observed histopathologically in the spleen, thymus, and Peyer's patches in the present study.

Hypoglycemic, Hypolipidemic, and Wound Healing Potential of Quercetin in Streptozotocin-Induced Diabetic Rats.

BACKGROUND: Among the dietary polyphenolic, quercetin is the most common compound available in vegetables and fruits. The phytochemicals are used to treat diabetic wounds and diabetes, and specifically dietary polyphenols are being extensively studied for their anti-inflammatory and antioxidant abilities. OBJECTIVE: The objective of the study was to assess the hypoglycemic, hypolipidemic, and wound healing potential of quercetin in streptozotocin (STZ)-induced diabetic Wistar rats. MATERIALS AND METHODS: Induction of diabetes was done by intraperitoneally administration of STZ at the dose of 55 mg/kg in Wistar rats. An excision wound was created in diabetic rats that were treated with quercetin (100 mg/kg) orally and quercetin ointment topically to evaluate the antidiabetic and wound healing potential of quercetin. RESULTS: Repeated oral administration of quercetin along with topical application of quercetin ointment in diabetic rats normalized the altered blood glucose, hydroxyproline, and glucosamine levels. Topical application of quercetin ointment alone on the excised wound was sufficient enough to heal the wound area in diabetic rats. CONCLUSIONS: The result of the present study indicates that quercetin produces hypoglycemic effect in STZ-induced diabetic rats and normalized plasma lipids and protein profiles. Besides, this quercetin also has an excellent wound healing property when applied topically on the wound area in diabetic rats. SUMMARY: Quercetin has hypoglycaemic and hypolipidemic potential in streptozotocin induced diabetes in wistar ratsDermal application along with oral administrations of quercetin has more effective in wound healing in diabetic animalsHistopathological studies of pancreas, skin and liver shows significant reduction in archaeological alterations on quercetin administrations in diabetic rats. Abbreviation used: STZ: Streptozotocin; CMC: Carboxy methyl cellulose; HDL: High density lipoproteins; LDL: low density lipoproteins.

BAY 41-2272 Treatment Improves Acetylcholine-Induced Aortic Relaxation in L-NAME Hypertensive Rats.

Hypertension, an emerging problem of recent era, and many pathophysiological factors are participating to produce the disease. Nitric oxide (NO) is an important constituent to ameliorate hypertensive condition. Inhibition of endogenous NO synthase by L-NG-Nitroarginine methyl ester (L-NAME) was responsible for generating hypertension in rats. BAY 41-2272 (5-cyclopropyl-2-[1-(2-fluoro-benzyl)-1H-pyrazolo[3,4-b]pyridine-3-yl]-pyrimidin-4-ylamine), a soluble guanylyl cyclase activator, restricts rise of blood pressure and shows cardioprotective activity. The aim of the present study was to analyze effect of short-term BAY 41-2272 treatment on blood pressure and vascular function. Male Wistar rats were randomly divided into three groups such as control (group-A), hypertensive (group-B), and BAY 41-2272-treated hypertensive (group-C) rats. Normal saline was administered intramuscularly to control rats for last 3 days (days 40, 41, and 42) of total 42 days treatment, whereas rats of group-B and group-C were treated with L-NAME hydrochloride in drinking water at 50 mg/kg body weight daily for 42 days. Also, normal saline and BAY 41-2272 were administered for last 3 days at two different dosages at 1 and 3 mg/kg body weight/day intramuscularly to group-B and group-C rats, respectively. Administration of BAY 41-2272 for 3 days was not sufficient enough to decrease mean arterial pressure of hypertensive rats significantly. BAY at both the treatment dosages significantly ameliorate acetylcholine-induced maximal aortic relaxation compared with BAY-untreated hypertensive rats. Findings of the present study indicate that even shorter period of BAY 41-2272 treatment (3 days) improves vascular relaxation.

Acetaminophen increases the risk of arsenic-mediated development of hepatic damage in rats by enhancing redox-signaling mechanism.

We evaluated whether the commonly used analgesic-antipyretic drug acetaminophen can modify the arsenic-induced hepatic oxidative stress and also whether withdrawal of acetaminophen administration during the course of long-term arsenic exposure can increase susceptibility of liver to arsenic toxicity. Acetaminophen was co-administered orally to rats for 3 days following 28 days of arsenic pre-exposure (Phase-I) and thereafter, acetaminophen was withdrawn, but arsenic exposure was continued for another 28 days (Phase-II). Arsenic increased lipid peroxidation and reactive oxygen species (ROS) generation, depleted glutathione (GSH), and decreased superoxide dismutase (SOD), catalase, glutathione peroxidase (GPx), and glutathione reductase (GR) activities. Acetaminophen caused exacerbation of arsenic-mediated lipid peroxidation and ROS generation and further enhancement of serum alanine aminotransferase and aspartate aminotransferase activities. In Phase-I, acetaminophen caused further GSH depletion and reduction in SOD, catalase, GPx and GR activities, but in Phase-II, only GPx and GR activities were more affected. Arsenic did not alter basal and inducible nitric oxide synthase (iNOS)-mediated NO production, but decreased constitutive NOS (cNOS)-mediated NO release. Arsenic reduced expression of endothelial NOS (eNOS) and iNOS genes. Acetaminophen up-regulated eNOS and iNOS expression and NO production in Phase-I, but reversed these effects in Phase-II. Results reveal that acetaminophen increased the risk of arsenic-mediated hepatic oxidative damage. Withdrawal of acetaminophen administration also increased susceptibility of liver to hepatotoxicity. Both ROS and NO appeared to mediate lipid peroxidation in Phase-I, whereas only ROS appeared responsible for peroxidative damage in Phase-II.

Subacute arsenic exposure through drinking water reduces the pharmacodynamic effects of ketoprofen in male rats.

We evaluated the modulatory role of the groundwater contaminant arsenic on the pharmacodynamic responses of the nonsteroidal analgesic-antipyretic drug ketoprofen and the major pro-inflammatory mediators linked to the mechanism of ketoprofen's therapeutic effects. Rats were pre-exposed to sodium arsenite (0.4, 4 and 40 ppm) through drinking water for 28 days. The pharmacological effects of orally administered ketoprofen (5 mg/kg) were evaluated the following day. Pain, inflammation and pyretic responses were, respectively, assessed through formalin-induced nociception, carrageenan-induced inflammation and lipopolysaccharide-induced pyrexia. Arsenic inhibited ketoprofen's analgesic, anti-inflammatory and antipyretic effects. Further, arsenic enhanced cyclooxygenase-1 and cyclooxygenase-2 activities and tumor necrosis factor-α, interleukin-1ß and prostaglandin-E(2) production in hind paw muscle. These results suggest a functional antagonism of ketoprofen by arsenic. This may relate to arsenic-mediated local release of tumor necrosis factor-α and interleukin-1ß, which causes cyclooxygenase induction and consequent prostaglandin-E(2) release. In conclusion, subacute exposure to environmentally relevant concentrations of arsenic through drinking water may aggravate pain, inflammation and pyrexia and thereby, may reduce the therapeutic efficacy of ketoprofen.

Wound healing activity of carbon monoxide liberated from CO-releasing molecule (CO-RM).

Wound microenvironment presents widespread oxidant stress, inflammation, and onslaught of apoptosis. Carbon monoxide (CO) exerts pleiotropic cellular effects by modulating intracellular signaling pathways which translate into cellular protection against oxidative stress, inflammation, and apoptosis. CO-releasing molecules (CO-RMs) deliver CO in a controlled manner without altering carboxyhemoglobin levels. This study observed a potential therapeutic value of CO in the wound healing by using tricarbonyldichlororuthenium (II) dimer (CO-releasing molecule (CO-RM)-2), as one of the novel CO-releasing agent. The effect of CO-RM-2 treatment was studied on wound contraction, glucosamine, hydroxyproline levels, and mRNA of cytokines/adhesion molecule in rats using a full-thickness cutaneous wound model and angiogenesis in chick chorioallantoic membrane (CAM) model. CO-RM-2 treatment increased cellular proliferation and collagen synthesis as evidenced by the increase in wound contraction and hydroxyproline and glucosamine contents. The mRNA expression of cytokines endorsed fast healing, as was indicated by the inhibition of pro-inflammatory adhesion molecules such as ICAM-1 and cytokine TNF-α and upregulation of anti-inflammatory cytokine IL-10. An ELISA assay of IL-10 and TNF-α cytokines revealed pro-healing modulation in excision wound by CO-RM-2 treatment. CO-RM significantly promoted the angiogenesis as compared to the iCO-RM group in vitro in CAM model demonstrating pro-angiogenic effects of CO-RM-2 in wound healing process. These results indicate that CO-RM-2 may have a potential application in the management of recalcitrant/obstinate wounds wherein, active wound healing is desired. This study also opens up a new area of research for the synthesis of novel CO-releasing molecules to be used for such purposes.

Atorvastatin prevents vascular hyporeactivity to norepinephrine in sepsis: role of nitric oxide and α1-adrenoceptor mRNA expression.

Hyporeactivity to vasoconstrictors is one of the clinical manifestations of sepsis in man and experimental animals. The objective of the investigation was to examine whether atorvastatin can prevent hyporeactivity to norepinephrine (NE) in mouse aorta in sepsis, and if so, what are the mechanisms involved. Sepsis in mice was induced by cecal ligation and puncture. The aorta was harvested for tension experiment, nitric oxide (NO) and cyclic guanosine monophosphate measurements, and inducible NO synthase (iNOS) and α(1D)-adrenoceptor mRNA expression studies. In comparison with sham-operated controls, sepsis significantly decreased the contractile response to NE in the mouse aorta. Pretreatment with atorvastatin of septic animals completely restored NE-induced contractions to levels similar to those of sham-operated controls and significantly increased survival time and mean arterial pressure. Atorvastatin also attenuated iNOS-induced overproduction of NO, as well as iNOS mRNA expression. Accordingly, hyporeactivity to NE was not evident in tissues pretreated with selective iNOS inhibitor 1400W in sepsis. Although basal cyclic guanosine monophosphate accumulation in the aorta was reduced in sepsis, pretreatment of the tissues with soluble guanylyl cyclase inhibitor 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (ODQ) partially restored the reactivity to NE. Interestingly, hyporeactivity to NE in sepsis was associated with a decreased α(1D)-adrenoceptor mRNA expression in the mouse aorta. Atorvastatin pretreatment, however, prevented the decrease in α(1D)-adrenoceptor mRNA expression in septic animals. In conclusion, atorvastatin seems to prevent hyporeactivity to vasoconstrictor NE in the aorta from septic mice through attenuation of overproduction of NO as well as improved α(1D)-adrenoceptor mRNA expression. The findings of the present study may explain the beneficial effects of atorvastatin on improved hemodynamic functions in sepsis.

Pro-healing potential of hemin: an inducer of heme oxygenase-1.

Hemin induces heme oxygenase (HO), an enzyme which degrades heme in a rate-limiting manner and has an important role in cellular protection against oxidative stress and apoptosis. This HO inducer may be of potential therapeutic value in wound healing and inflammation. To identify the beneficial activity of HO vis a vis wound healing, hemin was used as inducer of HO in rats using a full-thickness cutaneous wound model. Hemin treatment increased cellular proliferation and collagen synthesis as evidenced by increase in wound contraction and hydroxyproline and glucosamine contents. mRNA expression of cytokines endorsed fast healing as was indicated by inhibition of pro-inflammatory cytokines such as ICAM-1 and TNF-alpha and up-regulation of anti-inflammatory cytokine IL-10.

Induction of oxidative stress and lipid peroxidation in rats chronically exposed to cypermethrin through dermal application.

Present study was undertaken to study the effect of cypermethrin on oxidative stress after chronic dermal application. The insecticide was applied dermally at 50 mg/kg body weight in different groups of Wistar rats of either sex weighing 150-200 g. Significant (p < 0.05) increase in catalase activity was observed after 30 days of exposure. However, the superoxide dismutase activity declined significantly after 60 days of exposure. The activity of glutathione peroxidase and blood glutathione levels declined significantly (p < 0.05) after 30 days of cypermethrin dermal application. However, the activity of glutathione S-transferase increased significantly (p < 0.05) in all groups after 60 days of dermal exposure. Significant increase in lipid peroxidation was observed from 30 days onwards and reached a peak after 120 days of application.