prednisolone-hemisuccinate and Disease-Models--Animal

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

Candida albicans, normally found as a commensal in the gut, is a major human fungal pathogen responsible for both mucosal and systemic infections in a wide variety of immunocompromised individuals, including cancer patients and organ transplant recipients. The gastrointestinal tract represents a major portal of entry for the establishment of disseminated candidiasis in many of these individuals. Here we report the development of a diet-based mouse model for disseminated candidiasis acquired via the gastrointestinal tract. Using this model, as well as an appropriate immunosuppression regimen, we demonstrate that dissemination of C. albicans from the gastrointestinal tract can result in mortality within 30 days postinfection. We also show a significant increase in fungal burden in systemic organs, but not gastrointestinal tract organs, upon immunosuppression. Importantly, we demonstrate that the administration of two widely used antifungals, fluconazole and caspofungin, either pre- or postimmunosuppression, significantly reduces fungal burdens. This model should prove to be of significant value for testing the ability of both established and experimental therapeutics to inhibit C. albicans dissemination from the gastrointestinal tract in an immunocompromised host as well as the subsequent mortality that can result from disseminated candidiasis.

Topics: Animals; Antifungal Agents; Candida albicans; Candidiasis; Caspofungin; Colony Count, Microbial; Cyclophosphamide; Diet; Disease Models, Animal; Echinocandins; Fluconazole; Gastrointestinal Tract; Humans; Immunocompromised Host; Immunosuppressive Agents; Lipopeptides; Male; Mice; Mice, Inbred BALB C; Prednisolone; Survival Analysis

The influence of glucocorticoid (GC) on bone in rats at different ages was investigated in order to provide insight into human glucocorticoid induced osteoporosis (GCOP). Three-, 6-, and 12-month-old female Wistar rats were divided into four groups: Zero-time control (ZT), vehicle (Cont), prednisolone (PSL) 2 mg/kg (P-L), PSL 20 mg/kg (P-H). PSL was subcutaneously administered every day for 4 weeks. Bone mineral density (BMD) at the proximal metaphysis and diaphysis of the tibia was measured by peripheral quantitative computed tomography. Histomorphometry of the tibia was performed for 3- and 6-month-old rats. GC increased trabecular and cortical BMD at the metaphysis in all 3-month-old rats with time. Trabecular BMD at the metaphysis in the P-L and P-H groups was significantly higher than in the control group. Histomorphometric parameters for both bone formation and resorption were also increased by GC treatment. In the 6-month-old rats, the metaphyseal trabecular BMD did not significantly change in any group, but the diaphyseal trabecular BMD significantly increased in the control group with time. The trabecular BMD of the metaphysis and diaphysis was significantly lower in the P-L and P-H groups than in the control group at week 4. Histomorphometric parameters for bone formation and resorption were both reduced by GC treatment. The BMD remained unchanged in all 12-month-old rats. Six-month-old rats treated with 20 mg/kg GC are suitable models for GC-induced osteoporosis with dominant cancellous bone decrease and reduced bone turnover. The pathology induced by 20 mg/kg prednisolone in 6-month-old female rats seems to be most similar to glucocorticoid-induced osteoporosis in humans.

Topics: Animals; Bone Density; Bone Remodeling; Bone Resorption; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Glucocorticoids; Osteogenesis; Osteoporosis; Prednisolone; Rats; Rats, Wistar; Tibia; Tomography, X-Ray Computed

Peritoneal disturbances in the course of continuous ambulatory peritoneal dialysis (CAPD) are therapeutical relevant. Even calcifications are described in rarely cases. Concerning these cases an experimental model is known being created by Selye and belonging to the calciphylactic concept. In 8 female Wistar rats (weighing 140 to 180 g) this experiment was reproduced and in a similar series an inhibition was achieved by intraperitoneal application of a glucocorticoid. Experiments in this kind give a pathogenetic contribution for peritoneal disturbances and also possible therapeutic hints.

Topics: Animals; Calcinosis; Disease Models, Animal; Female; Injections, Intraperitoneal; Peritoneal Dialysis, Continuous Ambulatory; Peritoneal Diseases; Peritoneum; Prednisolone; Rats; Rats, Inbred Strains

Foreign materials were inserted into the hens' uteri and anti-inflammatory and immune suppressant drugs were used to determine possible causes of shell-less eggs. The presence of foreign shell-membranes and tampons in the uteri (shell glands) of hens caused a toxic shock-like syndrome ( TSLS ). Primary clinical signs were high fever, vomiting, diarrhea, and death. The presence of other materials, including inflated rubber balloons, had no adverse affect on the hens. Calcium carbonate deposits occurred on the surface of the balloons but not on other material inserted into the uteri. Injection of anti-inflammatory or immunosuppressive drugs did not increase shell weight in hens laying shell-less eggs. The hens' reproductive system was found to be sensitive in varying degrees to different types of foreign materials; thus, the avian female might serve as an animal model for studying toxic shock syndrome.

Topics: Animals; Calcification, Physiologic; Chickens; Cyclophosphamide; Disease Models, Animal; Egg Shell; Female; Foreign Bodies; Humans; Poultry Diseases; Prednisolone; Shock, Septic; Tampons, Surgical