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At least 1,099 records · Page 61Linked to original sources
PubMed2004

Heme-oxygenase-1 expression correlates with severity of acute cellular rejection in lung transplantation.

BACKGROUND: Heme-oxygenase-1 (HO-1) has been shown to play an important role in oxidative stress, and recent studies indicate that it is a graft survival protein in cardiac and liver transplant models. Our laboratory previously found HO-1 to be increased in human lung allografts with acute cellular rejection (ACR) and in active obliterative bronchiolitis. To better understand the role of HO-1 in ACR we studied the relationship between HO-1 expression and ACR in a rodent model of lung transplantation. STUDY DESIGN: Orthotopic left lung transplantation was performed from Lewis (donor) to Sprague-Dawley (recipient) rats, and ACR (Grade A0 to A4) was evaluated at days 3, 5, and 7. HO-1 expression was assessed by immunohistochemistry and Western analysis, and compared with the degree of ACR. Myeloperoxidase staining was evaluated as an indirect measure of oxidant stress. Donors and recipients were also treated with either an inhibitor of HO activity, tin protoporphyrin or an inducer, cobalt protoporphyrin, and the severity of ACR was compared with that in untreated allografts. RESULTS: HO-1 expression was elevated in transplanted versus native lungs or isografts, and the degree of elevation was closely correlated with ACR grade (p < 0.001). Similarly, myeloperoxidase expression increased with time and severity of ACR. Administration of the metalloporphyrins, tin protoporphyrin and cobalt protoporphyrin, produced no significant difference in the degree of ACR, but did alter the severity of ischemia-reperfusion injury. CONCLUSIONS: Similar to what occurs in human lung transplantation, HO-1 expression is increased in a rodent lung transplant model of ACR and correlates with the severity of rejection. Altering its expression does not appear to affect the degree of ACR.

Animals↗
PubMed1999

Prodrugs of CL316243: a selective beta3-adrenergic receptor agonist for treating obesity and diabetes.

CL316243 is a highly selective and potent beta3-adrenergic receptor agonist, and has been shown in rodent models to be an effective agent for treating obesity and Type II diabetes. To improve the oral absorption and pharmacokinetic profiles of CL316243, a number of prodrugs have been synthesized and evaluated. Several ester-type prodrugs show significant improvements in oral bioavailability in both rodent and primate models.

Adrenergic beta-Agonists↗
PubMed2004

A novel rodent neck pain model of facet-mediated behavioral hypersensitivity: implications for persistent pain and whiplash injury.

Clinical, epidemiological, and biomechanical studies suggest involvement of cervical facet joint injuries in neck pain. While bony motions can cause injurious tensile facet joint loading, it remains speculative whether such injuries initiate pain. There is currently a paucity of data explicitly investigating the relationship between facet mechanics and pain physiology. A rodent model of tensile facet joint injury has been developed using a customized loading device to apply two separate tensile deformations (low, high; n = 5 each) across the C6/C7 joint, or sham (n = 6) with device attachment only. Microforceps were rigidly coupled to the vertebrae for distraction and joint motions tracked in vivo. Forepaw mechanical allodynia was measured postoperatively for 7 days as an indicator of behavioral sensitivity. Joint strains for high (33.6 +/- 3.1%) were significantly elevated (P < 0.005) over low (11.1 +/- 2.3%). Digitization errors (0.17 +/- 0.20%) in locating bony markers were small compared to measured strains. Allodynia was significantly elevated for high over low and sham for all postoperative days. However, allodynia for low injury was not different than sham. A greater than three-fold increase in total allodynia resulted for high compared to low, corresponding to the three-fold difference in injury strain. Findings demonstrate tensile facet joint loading produces behavioral sensitivity that varies in magnitude according to injury severity. These results suggest that a facet joint tensile strain threshold may exist above which pain symptoms result. Continued investigation into the relationship between injury mechanics and nociceptive physiology will strengthen insight into painful facet injury mechanisms.

Analysis of Variance↗
PubMed1998

Regeneration through long nerve grafts in the swine model.

We investigated regeneration across a long nerve defect in the swine model to study extensive neural loss and long nerve gap. Most experiments have been conducted in the rodent model that, while an appropriate immunological model, only allows short nerve gaps to be studied. Twelve outbred swine received either an 8-cm ulnar nerve autograft or an allograft without immunosuppression. At 6 and 10 months, histomorphometry of the autografts demonstrated excellent nerve regeneration, while very poor regeneration was noted across the allografts. This confirmed that 8 cm are an adequate challenge independent of the spontaneous regeneration potential of axons seen in rodents. The swine ulnar nerve graft model causes minimal morbidity and will now be used with immunological manipulation of inbred animals.

Animals↗
PubMed2002

Cryopreserved cells isolated from the adult canine olfactory bulb are capable of extensive remyelination following transplantation into the adult rat CNS.

Naturally occurring spinal cord injury in dogs provides a potentially powerful intermediate model for testing the efficacy of therapeutic strategies developed in experimental rodent models before phase 1 trials in human patients. A particularly promising strategy involves transplantation of olfactory ensheathing cells (OECs) that both promote axon regeneration and generate new myelin sheaths. As a first step in developing OEC transplantation in the canine intermediate model we describe the isolation, purification, and characterization of OECs from adult dog olfactory bulb. We also show that the canine OEC behaves in a manner similar to its rodent counterpart following transplantation into demyelinating lesions in rat spinal cord and that these properties are retained following cryopreservation.

Animals↗
PubMed2004

Use of genetic mouse models in the study of diabetic nephropathy.

The study of experimental diabetic nephropathy in rodent models has led to many changes in the clinical management of human diabetic nephropathy. With the development of technology to generate knockout and transgenic animals, the mouse has become a favored species in medical research. There are several genetic mouse models of diabetes, with the majority being models of type 2 diabetes mellitus. These include the hypoinsulinemic non-obese diabetic mouse, the Kkay mouse, the New Zealand obese mouse, the hyperinsulinemic ob/ob mouse, and the different strains of obese hyperinsulinemic db/db mouse. Each of these models displays some renal changes, but by far the best model of renal disease and the one that is the most studied is the db/db mouse. The db/db mouse displays substantial glomerular pathology, including mesangial matrix expansion and modest albuminuria. It has been reported that the db/db mouse has a decline in creatinine clearance after 5 months of age, but more specific approaches are warranted to confirm these findings. A number of intervention studies show renoprotection in this model. Although mice have many advantages, such as being able to be cross-bred with genetically manipulated animals, in many ways they are not very similar to humans, and in some respects the rat may be a better choice, particularly in relation to some features of end-organ injury.

Animals↗
PubMed2004

Use of genetic mouse models in the study of diabetic nephropathy.

The study of experimental diabetic nephropathy in rodent models has led to many changes in the clinical management of human diabetic nephropathy. With the development of technology to generate knockout and transgenic animals, the mouse has become a favored species in medical research. There are several genetic mouse models of diabetes, with the majority being models of type 2 diabetes mellitus. These include the hypoinsulinemic nonobese diabetic mouse, the KKAy mouse, the New Zealand obese mouse, the hyperinsulinemic ob/ob mouse, and the different strains of obese hyperinsulinemic db/db mouse. Each of these models displays some renal changes, but by far the best model of renal disease and the one that is the most studied is the db/db mouse. The db/db mouse displays substantial glomerular pathology, including mesangial matrix expansion and modest albuminuria. It has been reported that the db/db mouse has a decline in creatinine clearance after 5 months of age, but more specific approaches are warranted to confirm these findings. A number of intervention studies show renoprotection in this model. Although mice have many advantages, such as being able to be crossbred with genetically manipulated animals, in many ways they are not very similar to humans, and in some respects the rat may be a better choice, particularly in relation to some features of end-organ injury.

Animals↗
PubMed2005

Autoimmune tolerance eliminates relapses but fails to halt progression in a model of multiple sclerosis.

To date there has been poor translation of immunotherapies from rodent models to treatment of progressive multiple sclerosis (MS). In the robust, relapsing Biozzi ABH mouse model of MS, using a combination of a transient deletion of T cells followed by intravenous (i.v.) myelin antigen administration, established relapsing disease in EAE can be effectively silenced. However, when treatment was initiated in late stage chronic-relapsing disease, despite inhibition of further relapses, mice demonstrated evidence of disease progression shown by a deterioration in mobility and development of spasticity and indicates that targeting relapsing, immunological components of MS alone is unlikely to be sufficient to control progression in the late stages of MS.

Adoptive Transfer↗
PubMed2002

Gene array profiling and immunomodulation studies define a cell-mediated immune response underlying the pathogenesis of alopecia areata in a mouse model and humans.

Alopecia areata is a suspected autoimmune hair loss disease. In a rodent model, alopecia areata can be induced in normal haired C3H/HeJ mice by transfer of skin grafts from mice with spontaneous alopecia areata. At weeks 2, 4, 6, and 10 after surgery, grafted mice were euthanized, skin collected and processed for histology, and RNA extracted. Age-matched sham-grafted mice, and mice with and without spontaneous alopecia areata, were similarly processed. For comparison, skin biopsies from alopecia areata and androgenetic alopecia affected humans were also collected. Skin mRNA processed to cDNA was analyzed using Affymetrix mouse 11K and human 6800 gene chip(R) array technology. Microarray results indicated 42 known genes upregulated or downregulated during onset of mouse alopecia areata consistent with an inflammatory cell-mediated disease pathogenesis involving antigen presentation, costimulation, and a T helper 1 lymphocyte response. In contrast, 114 genes, many regulating immunoglobulin response, were altered late in disease development. In alopecia areata affected humans, 95 genes were significantly modulated. As confirmation of microarray analysis results, lymph node and spleen cells from alopecia areata affected mice injected into normal haired littermates transferred the alopecia areata phenotype. Alopecia areata onset could be inhibited in skin-grafted mice by modulation with B7.1- and B7.2-specific monoclonal antibodies. In addition, depletion of CD4+ CD8+ expressing cells in chronic alopecia areata affected mice using monoclonal antibodies permitted hair regrowth. The results consistently demonstrated the importance of an immune cell-mediated disease mechanism in alopecia areata pathogenesis and suggested targeting antigen-presenting cells and reactive lymphocytes may be effective in alopecia areata treatment.

Adoptive Transfer↗
PubMed1999

Development of a transgenic mouse model for carcinogenesis bioassays: evaluation of chemically induced skin tumors in Tg.AC mice.

Transgenic rodent models have emerged as potentially useful tools in the assessment of drug and chemical safety. The transgenic Tg.AC mouse carries an inducible v-Ha-ras oncogene that imparts the characteristic of genetically initiated skin to these animals. The induction of epidermal papillomas in the area of topically applied chemical agents, for duration of not more than 26 weeks, acts as a reporter phenotype that defines the activity of the test article. We describe here the activity of six chemicals that have been previously characterized for activity in the standard 2-year bioassay conducted by the National Toxicology Program (NTP). Homozygous female Tg.AC mice were treated with benzene (BZ), benzethonium chloride (BZTC), o-benzyl-p-chlorophenol (BCP), 2-chloroethanol (2-CE), lauric acid diethanolamine (LADA) and triethanolamine (TEA). BZ and LADA induced skin papillomas in a dose-dependent manner, while BCP induced papillomas only at the highest dose. BZTC, 2-CE, and TEA exhibited no activity. The correspondence of chemical activity in Tg.AC mice with that in the 2-year bioassay was high. A comparison of responsiveness to BZ and LADA was made between hemizygous and homozygous female Tg.AC mice. Both genotypes appear to be equally sensitive to maximum doses of active compounds. The results reported here indicate that the Tg.AC transgenic mouse model can discriminate between carcinogens and noncarcinogens and that both mutagenic and nonmutagenic chemicals can be detected. These studies provide support for the adjunctive use of the Tg.AC transgenic mouse skin tumor model in drug and chemical safety assessment and for the prediction of the carcinogenic potential of chemicals.

Animals↗
PubMed2006

Defining high-fat-diet rat models: metabolic and molecular effects of different fat types.

High-fat (HF)-diet rodent models have contributed significantly to the analysis of the pathophysiology of the insulin resistance syndrome, but their phenotype varies distinctly between different studies. Here, we have systematically compared the metabolic and molecular effects of different HF with varying fatty acid compositions. Male Wistar rats were fed HF diets (42% energy; fat sources: HF-L - lard; HF-O - olive oil; HF-C - coconut fat; HF-F - fish oil). Weight, food intake, whole-body insulin tolerance and plasma parameters of glucose and lipid metabolism were measured during a 12-week diet course. Liver histologies and hepatic gene expression profiles, using Affymetrix GeneChips, were obtained. HF-L and HF-O fed rats showed the most pronounced obesity and insulin resistance; insulin sensitivity in HF-C and HF-F was close to normal. Plasma omega-3 polyunsaturated fatty acid (omega-3-PUFA) and saturated fatty acid (C(12)-C(14), SFA) levels were elevated in HF-F and HF-C animals respectively. The liver histologies showed hepatic steatosis in HF-L, HF-O and HF-C without major inflammation. Hepatic SREBP1c-dependent genes were upregulated in these diets, whereas PPARalpha-dependent genes were predominantly upregulated in HF-F fed rats. We detected classical HF effects only in diets based on lard and olive oil (mainly long-chain, saturated (LC-SFA) and monounsaturated fatty acids (MUFA)). PUFA- or MC-SFA-rich diets did not induce insulin resistance. Diets based on LC-SFA and MUFA induced hepatic steatosis with SREBP1c activation. This points to an intact transcriptional hepatic insulin effect despite resistance to insulin's metabolic actions.

Animals↗
PubMed2005

Review of the potential photo-cocarcinogenicity of topical calcineurin inhibitors: position statement of the European Dermatology Forum.

Topical Calcineurin Inhibitors (TCIs) used for the treatment of atopic eczema modify the immune regulatory function of the skin and may have the potential to enhance immunosuppressive ultraviolet (UV) effects. Current recommendations on UV protection in eczema patients treated with PCIs are inconsistent and have given rise to uncertainty and anxiety in patients. Therefore, the European Dermatology Forum (EDF) developed a position statement which reviews critically the available data with regard to the problem, especially analysing and commenting the limitations of rodent models for the human situation. There is no conclusive evidence from rodent trials to indicate that long-term application of TCIs is photococarcinogenic. There is a need for further studies to investigate the validity of mouse models as well as long-term cohort studies in patients using TCIs. Available data suggest that long-term application of TCIs is safe, that there is no evidence of increased skin cancer risk and that it is ethical to treat patients with TCIs when indicated.

Administration, Topical↗
PubMedDate not supplied

Neuroprotective effects of estrogens: potential mechanisms of action.

Epidemiological studies associate post-menopausal estrogen use with a reduction in risk of Alzheimer's disease, a reduction in risk of Parkinson's disease, and death from stroke. The neuroprotective efficacy of estrogens have been well described and may contribute to these clinical effects. Estrogen-mediated neuroprotection has been described in several neuronal culture model systems with toxicities including serum-deprivation, beta-amyloid-induced toxicity, excitotoxicity, and oxidative stress. In animal models, estrogens have been shown to attenuate neuronal death in rodent models of cerebral ischemia, traumatic injury, and Parkinson's disease. Although estrogens are known to exert several direct effects on neurons, the cellular mechanisms behind the neuroprotective efficacy of the steroid are only beginning to be elucidated. In this review, we summarize the data supporting a neuroprotective role for estrogens in both culture and animal models and discuss neuronal effects of estrogens that may contribute to the neuroprotective effects. These effects include activation of the nuclear estrogen receptor, altered expression of bcl-2 and related proteins, activation of the mitogen activated kinase pathway, activation of cAMP signal transduction pathways, modulation of intracellular calcium homeostasis, and direct antioxidant activity.

Animals↗
PubMedDate not supplied

Prediction of chemical carcinogenicity from molecular structure.

Carcinogens represent a serious threat to human health. In vivo determination of carcinogenicity is time-consuming and expensive, thus in silico models to predict chemical carcinogenicity are highly desirable for virtual screening of compound libraries of both pharmaceutically and other commercially interesting molecules. In the present study, a PLS-DA (partial least squares discriminant analysis) model was developed to predict carcinogenicities in each of four rodent models: male mouse (MM), female mouse (FM), male rat (MR), and female rat (FR). The data set that was used contained over 520 compounds from both the NTP and the FDA databases. All the models were built from the same molecular descriptor system, which is based on atom typing [Sun, H. J. Chem. Inf. Comput. Sci. 2004, 44, 748-757], enabling the comparison of atomic contributions to carcinogenicity with respect to species and gender. Using four components, the models were able to achieve excellent fitting and prediction, with r(2) = 0.987 and q(2) = 0.944 for MM, r(2) = 0.985 and q(2) = 0.950 for FM, r(2) = 0.989 and q(2) = 0.962 for MR, and r(2) = 0.990 and q(2) = 0.965 for FR. The models were further validated by response permutation testing and external validation, and the results indicated that the models were both statistically significant and predictive. Variable influence on projection (VIP) analysis identified the key atom types and fragments that contributed to carcinogenicities and response differences across species and gender.

Animals↗
PubMed1992

Dihydrolipoate reduces neuronal injury after cerebral ischemia.

It has been shown in vitro that dihydrolipoate (DL-6,8-dithioloctanoic acid) has antioxidant activity against microsomal lipid peroxidation. We tested dihydrolipoate for its neuroprotective activity using models of hypoxic and excitotoxic neuronal damage in vitro and rodent models of cerebral ischemia in vivo. In vitro, neuronal damage was induced in primary neuronal cultures derived form 7-day-old chick embryo telencephalon by adding either 1 mM cyanide or 1 mM glutamate to the cultures. Cyanide-exposed and dihydrolipoate-treated (10(-9)-10(-7) M) cultures showed an increased protein and ATP content compared with controls. The glutamate-exposed cultures treated with dihydrolipoate (10(-7)-10(-5) M) showed a decreased number of damaged neurons. In vivo, dihydrolipoate treatment (50 and 100 mg/kg) reduced brain infarction after permanent middle cerebral artery occlusion in mice and rats. Dihydrolipoate treatment (50 and 100 mg/kg) could not ameliorate neuronal damage in the rat hippocampus or cortex caused by 10 min of forebrain ischemia. A comparable neuroprotection was obtained by using dimethylthiourea, both in vitro (10(-7) and 10(-6) M) and at a dose of 750 mg/kg in the focal ischemia models. Lipoate, the oxidized form of dihydrolipoate, failed to reduce neuronal injury in any model tested. We conclude that dihydrolipoate, similarly to dimethylthiourea, is able to protect neurons against ischemic damage by diminishing the accumulation of reactive oxygen species within the cerebral tissue.

Animals↗
PubMed2002

Ocular disease in rats: a review.

The rat Rattus norvegicus is widely used in experimental work, both providing a rodent model for human ocular disease and as a species for toxicologic screening. In addition, the rat is more and more widely kept as a pet, being both friendly and intelligent. Diagnosis and treatment of ocular disease is important for the welfare of individual animals and whole colonies, but also to ensure that spontaneous disease is not compromising experimental work. Here, ophthalmic conditions are reviewed in order to provide a survey of ocular disease in the rat both for veterinary ophthalmologists and for laboratory animal veterinarians and research workers.

Animals↗
PubMedDate not supplied

Chromaffin cell transplants for alleviation of chronic pain.

Treatment of intractable pain with parenteral, subarachnoid, or epidural narcotics is often unsatisfactory due to tolerance and other systemic complications that accompany increasing dosages of these drugs. Other disadvantages include the potential infections with implantable pumps and the inconvenience of repeated narcotic administration. During the past several years, studies at the author's laboratory indicated that transplantation of adrenal medullary tissue or isolated chromaffin cells into the spinal subarachnoid space can significantly reduce pain in several rodent models without resulting in development of tolerance. Adrenal medullary chromaffin cells were selected because they produce high levels of both opioid peptides and catecholamines, agents that independently, and possibly synergistically, reduce pain when injected locally into the spinal subarachnoid space. The adrenal medullary transplants survive for prolonged periods, and continue to produce high levels of both catecholamines and met-enkephalin. These transplants reduce pain in two rodent chronic pain models, an arthritis model and a peripheral neuropathy model, both of which closely resemble human chronic pain syndromes. The success of the animal studies has led to initiation of human clinical trials in patients with chronic cancer pain; results are promising.

Adrenal Medulla↗
PubMed2004

Ultrasound vocalisation by rodents does not correlate with behavioural measures of persistent pain.

Three well-established rodent models of somatic, visceral and neuropathic pain were used to test the hypothesis that a stress and anxiety evoked behaviour, namely ultrasound vocalisation, correlates with other well-characterised indices of pain behaviour, such as limb withdrawal and stereotypical behaviour. Persistent pain presents a significant clinical problem for which there remains relatively ineffective clinical management and animal models of pain are commonly employed to investigate the underlying pathophysiology and for pre-clinical evaluation of novel therapies. At present, the assessment of such animal models largely relies on the observation of simple reflex responses which may not entirely represent the full range of rodent pain behaviour. Therefore, additional integrated behavioural indices for the quantification of pain could improve the veracity of animal models. In stressful or harmful situations, it is thought that rodents produce ultrasound vocalisations to communicate within the social group. In this study, the number of ultrasound vocalisations (22 kHz) was measured during both evoked and ongoing pain. Ultrasound vocalisation was not associated with other pain behaviour in any of the inflammatory, visceral or neuropathic pain models examined and is therefore not a useful integrated correlate of pain behaviour.

Animals↗