chlortetracycline 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

β-Diketone antibiotics (DKAs) are widely used in human and veterinary medicine to prevent and treat a large variety of infectious diseases. Long-term DKA exposure to zebrafish can result in lipid metabolism disorders and liver function abnormalities. Based on our previous miRNA-seq analyses, miR-144 and miR-125b were identified as target genes regulating lipid metabolism. DKA-exposure at 12.5 and 25 mg/L significantly increased the expressions of miR-144 and miR-125b. The expression levels for the two miRNAs exhibited an inverse relationship with their lipid-metabolism-related target genes (ppardb, bcl2a, pparaa and pparda). Over-expression and inhibition of miR-144 and miR-125b were observed by micro-injection of agomir-144, agomir-125b, antagomir-144 and antagomir-125b. The over-expression of miR-144 and miR-125b enhanced lipid accumulation and further induced lipid-metabolism-disorder syndrome in F1-zebrafish. The expression of ppardb and bcl2a in whole-mount in situ hybridization was in general agreement with results from qRT-PCR and was concentration-dependent. Oil red O and H&E staining, as well as related physiological and biochemical indexes, showed that chronic DKA exposure resulted in lipid-metabolism-disorder in F0-adults, and in F1-larvae fat accumulation, increased lipid content, abnormal liver function and obesity. The abnormal levels of triglyceride (TG) and total cholesterol (TCH) in DKA-exposed zebrafish increased the risk of hyperlipidemia, atherosclerosis and coronary heart disease. These observations improve our understanding of mechanisms leading to liver disease from exposure to environmental pollution, thereby having relevant practical significance in health prevention, early intervention, and gene therapy for drug-induced diseases.

Topics: Animals; Anti-Bacterial Agents; Atherosclerosis; Chlortetracycline; Cholesterol; Ciprofloxacin; Computational Biology; Disease Models, Animal; Doxycycline; Enrofloxacin; Female; Hyperlipidemias; Larva; Lipid Metabolism; Male; MicroRNAs; Ofloxacin; Oxytetracycline; Peroxisome Proliferator-Activated Receptors; Triglycerides; Up-Regulation; Zebrafish; Zebrafish Proteins

Subtherapeutic antibiotics have been widely used in agriculture since the 1950s, which can be accumulated in human body through various approaches and may have long-term consequences. However, there is limited information about the link between chronic subtherapeutic antibiotic exposure and the outcome of ischemic brain injury. Here we showed that long-term treatment with subtherapeutic chlortetracycline, penicillin or vancomycin, which were widely used in agriculture approved by US Food and Drug Administration (FDA), could impair EPC functions, reduce ischemic brain angiogenesis and aggravate cerebral ischemic injury and long-term stroke outcomes in mice. In addition, transplantated EPCs from chronic antibiotic-treated mice showed a lower therapeutic effect on cerebral ischemic injury reduction and local angiogenesis promotion compared to those from control mice, and EPCs from the donor animals could integrate into the recipient ischemic brain in mice. Furthermore, transplanted EPCs might exert paracrine effects on cerebral ischemic injury reduction in mice, which could be impaired by chronic antibiotic exposure. In conclusion, chronic subtherapeutic antibiotic exposure aggravated cerebral ischemic injury in mice, which might be partly attributed to the impairment of both EPC-mediated angiogenesis and EPCs' paracrine effects. These findings reveal a previously unrecognized impact of chronic subtherapeutic antibiotic exposure on ischemic injury.

Topics: Animals; Anti-Bacterial Agents; Brain Ischemia; Chlortetracycline; Disease Models, Animal; Endothelial Progenitor Cells; Mice; Neovascularization, Physiologic; Penicillins; Stroke; Vancomycin

The objective of this study is to characterize arterial tissue with and without atherosclerosis by fluorescence lifetime imaging microscopy (FLIM) using Europium Chlortetracycline complex (EuCTc) as fluorescent marker. For this study, twelve rabbits were randomly divided into a control group (CG) and an experimental group (EG), where they were fed a normal and hypercholesterolemic diet, respectively, and were treated for 60 days. Cryosections of the aortic arch specimens were cut in a vertical plane, mounted on glass slides, and stained with Europium (Eu), Chlortetracycline (CTc), Europium Chlortetracycline (EuCTc), and Europium Chlortetracycline Magnesium (EuCTcMg) solutions. FLIM images were obtained with excitation at 405 nm. The average autofluorescence lifetime within plaque depositions was ~1.36 ns. Reduced plaque autofluorescence lifetimes of 0.23 and 0.31 ns were observed on incubation with EuCTc and EuCTcMg respectively. It was observed a quenching of collagen, cholesterol and TG emission spectra increasing EuCTc concentration. The drastic reduction in fluorescence lifetimes is due to a resonant energy transfer between collagen, triglycerides, cholesterol and europium complexes, quenching fluorescence.

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Atherosclerosis; Chlortetracycline; Cholesterol, Dietary; Collagen; Disease Models, Animal; Energy Transfer; Europium; Fluorescent Dyes; Microscopy, Fluorescence; Plaque, Atherosclerotic; Rabbits; Time Factors; Triglycerides

Tetracyclines have been shown to have anti-inflammatory effects in addition to their antimicrobial action. We investigated the effects of in vivo administration of chlortetracycline (CTC) on ex vivo perfused pig livers. The retention and clearance of Salmonella choleraesuis, production of acute phase proteins C-reactive protein (CRP), and haptoglobin (HPG) by whole livers were studied. The in vitro modulation by CTC of TNF-alpha secretion by pig Kupffer cells (KC) was also studied. Pigs were dosed orally with CTC for three days, and given injections of Salmonella LPS 24 h before removal of the liver. Salmonella retention and clearance by livers of pigs given CTC was lower than by control livers (p < 0.01 and p < 0.05, respectively). We demonstrated an increase of CRP and HPG by livers from control pigs after a three-hour perfusion while pigs from CTC pretreated pigs varied in this response. Further, CTC decreased the secretion of TNF-alpha by cultured KC incubated in vitro with LPS. Modulation of TNF-alpha production by CTC suggests a potential for attenuating the inflammatory response. However, this possible beneficial action of CTC was accompanied by a significant decline in the antimicrobial effect of the liver.

Topics: Acute-Phase Reaction; Animals; Anti-Bacterial Agents; C-Reactive Protein; Chlortetracycline; Disease Models, Animal; Haptoglobins; Kupffer Cells; Liver; Perfusion; Salmonella; Salmonella Infections, Animal; Swine; Swine Diseases; Tumor Necrosis Factor-alpha

The in vivo antibacterial effectiveness in the rabbit cornea of a number of commercially available ophthalmic antibiotic preparations was determined against a single strain of penicillinase-producing Staphylococcus aureus isolated from a human corneal ulcer. Each antibiotic was instilled topically at hourly intervals, and the number of residual viable organisms in the cornea subsequently was ascertained. In vivo measurements demonstrated that five antibiotics--neomycin sulfate, gentamicin sulfate, erythromycin, tetracycline hydrochloride, and chlortetracycline hydrochloride--were equally effective in suppressing growth of the strain of S aureus studied. Therapeutic results were the same whether the corneal epithelium was present of absent for each of the drugs studied. With one exception (chloramphenicol), there was excellent correlation between in vivo and in vitro findings.

Topics: Administration, Topical; Animals; Anti-Bacterial Agents; Chlortetracycline; Disease Models, Animal; Erythromycin; Gentamicins; Humans; In Vitro Techniques; Keratitis; Neomycin; Ophthalmic Solutions; Rabbits; Staphylococcal Infections; Staphylococcus aureus; Tetracycline

A technique for inducing pneumococcal meningitis in mice and a description of the histopathologic changes that accompany this experimentally produced disease are provided in the present report. This infection of mice was investigated to determine whether it could serve as a suitable model for detecting agents that have potential therapeutic utility in bacterial meningitis in man. 21 antibiotics, belonging to six major classes were evaluated for efficacy in the experimental infection. The three most active agents proved to be amoxicillin, cephaloridine, and chlortetracycline. Up to this time, amoxicillin has not been commercially available as an injectable dosage form. However, in view of the compound's outstanding efficacy in the present experiments, it would be desirable to investigate its effectiveness in the naturally occurring disease in man.

Topics: Animals; Anti-Bacterial Agents; Cephalosporins; Cerebellum; Cerebral Cortex; Chloramphenicol; Chlortetracycline; Demeclocycline; Disease Models, Animal; Erythromycin; Lincomycin; Male; Meningitis, Pneumococcal; Mice; Penicillins; Rolitetracycline; Streptococcus pneumoniae; Tetracycline; Virulence

Topics: Administration, Oral; Animal Feed; Animals; Antibodies, Bacterial; Antibody Formation; Chlortetracycline; Complement Fixation Tests; Disease Models, Animal; Hemagglutination Tests; Mycoplasma; Mycoplasma Infections; Pneumonia; Swine; Swine Diseases

Topics: Ammonia; Animals; Anti-Bacterial Agents; Ascorbic Acid; Bacitracin; Chloramphenicol; Chlortetracycline; Demeclocycline; Depression, Chemical; Disease Models, Animal; Enzyme Repression; Erythromycin; Female; Hydroxamic Acids; In Vitro Techniques; Intestines; Kanamycin; Male; Neomycin; Niacinamide; Oxytetracycline; Penicillin G; Rats; Streptomycin; Sulfamethoxypyridazine; Sulfisoxazole; Sulfonamides; Tetracycline; Urease

Topics: Animals; Bartonella Infections; Chickens; Chlortetracycline; Disease Models, Animal; Oxytetracycline; Rolitetracycline; Tetracycline