scholarly journals Establishment of a Chronic Trypanosoma Equiperdum Infection Model in Mice

2020 ◽  
Author(s):  
Yusuke Tanaka ◽  
Keisuke Suganuma ◽  
Kenichi Watanabe ◽  
Yoshiyasu Kobayashi
Keyword(s):  
Chronic Infection ◽  
Histopathological Examination ◽  
Experimental Studies ◽  
Clinical Signs ◽  
Disease Process ◽  
Infection Model ◽  
Sequential Method ◽  
Trypanosoma Equiperdum

Abstract Dourine, caused by chronic infection with Trypanosoma equiperdum, is one of the African trypanosomiasis in equids. Since the pathogenesis of dourine has not yet been elucidated, experimental studies using mouse infection models are needed. However, mice cannot be infected with most T. equiperdum strains or rapidly develop parasitemia if infection is established and die within a few days. A sequential method of isolating parasites from dourine-affected horses and adapting them to in vitro cultures using soft agarose media was recently developed. Various T. equiperdum strains adapted to in vitro conditions have since been established using this technique. We used one of these strains, the T. equiperdum IVM-t2 strain. In the present study, we inoculated mice with the IVM-t2 strain and successfully produced a chronic infection model in mice. In the clinical examination, periodic parasitemia and skin plaques, which are characteristic clinical signs of dourine-affected horses, were observed. A histopathological examination revealed that some of the lesions observed in infected horses, such as vaginitis, trypanosomal sand, and peripheral neuritis, were reproduced in mice. This mouse model will be a valuable tool for pathological, immunological, and parasitological in vivo research, and will contribute to investigations on the mechanisms underlying the disease process and the host-protozoa relationship.

scholarly journals Evaluation of Arylimidamides DB1955 and DB1960 as Candidates against Visceral Leishmaniasis and Chagas' Disease:In VivoEfficacy, Acute Toxicity, Pharmacokinetics, and Toxicology Studies

2012 ◽  
Vol 56 (7) ◽  
pp. 3690-3699 ◽  
Author(s):  
Xiaohua Zhu ◽  
Qiang Liu ◽  
Sihyung Yang ◽  
Toufan Parman ◽  
Carol E. Green ◽  
...  
Keyword(s):  
Visceral Leishmaniasis ◽  
Histopathological Examination ◽  
Clinical Signs ◽  
Infection Model ◽  
High Dose ◽  
Repeat Dose ◽  
Dosing Regimen ◽  
Peak Parasitemia

ABSTRACTArylimidamides (AIAs) have shown outstandingin vitropotency against intracellular kinetoplastid parasites, and the AIA 2,5-bis[2-(2-propoxy)-4-(2-pyridylimino)aminophenyl]furan dihydrochloride (DB766) displayed goodin vivoefficacy in rodent models of visceral leishmaniasis (VL) and Chagas' disease. In an attempt to further increase the solubility andin vivoantikinetoplastid potential of DB766, the mesylate salt of this compound and that of the closely related AIA 2,5-bis[2-(2-cyclopentyloxy)-4-(2-pyridylimino)aminophenyl]furan hydrochloride (DB1852) were prepared. These two mesylate salts, designated DB1960 and DB1955, respectively, exhibited dose-dependent activity in the murine model of VL, with DB1960 inhibiting liver parasitemia by 51% at an oral dose of 100 mg/kg/day × 5 and DB1955 reducing liver parasitemia by 57% when given by the same dosing regimen. In a murineTrypanosoma cruziinfection model, DB1960 decreased the peak parasitemia levels that occurred at 8 days postinfection by 46% when given orally at 100 mg/kg/day × 5, while DB1955 had no effect on peak parasitemia levels when administered by the same dosing regimen. Distribution studies revealed that these compounds accumulated to micromolar levels in the liver, spleen, and kidneys but to a lesser extent in the heart, brain, and plasma. A 5-day repeat-dose toxicology study with DB1960 and DB1955 was also conducted with female BALB/c mice, with the compounds administered orally at 100, 200, and 500 mg/kg/day. In the high-dose groups, DB1960 caused changes in serum chemistry, with statistically significant increases in serum blood urea nitrogen, lactate dehydrogenase, aspartate aminotransferase, and alanine aminotransferase levels, and a 21% decrease in body weight was observed in this group. These changes were consistent with microscopic findings in the livers and kidneys of the treated animals. The incidences of observed clinical signs (hunched posture, tachypnea, tremors, and ruffled fur) were more frequent in DB1960-treated groups than in those treated with DB1955. However, histopathological examination of tissue samples indicated that both compounds had adverse effects at all dose levels.

scholarly journals Diabetic Cataract—Pathogenesis, Epidemiology and Treatment

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Andreas Pollreisz ◽  
Ursula Schmidt-Erfurth
Keyword(s):  
Experimental Studies ◽  
Disease Process ◽  
Basic Research ◽  
Polyol Pathway ◽  
Population Based ◽  
Diabetic Patients ◽  
Diabetic Cataract ◽  
Cataract Development

Cataract in diabetic patients is a major cause of blindness in developed and developing countries. The pathogenesis of diabetic cataract development is still not fully understood. Recent basic research studies have emphasized the role of the polyol pathway in the initiation of the disease process. Population-based studies have greatly increased our knowledge concerning the association between diabetes and cataract formation and have defined risk factors for the development of cataract. Diabetic patients also have a higher risk of complications after phacoemulsification cataract surgery compared to nondiabetics. Aldose-reductase inhibitors and antioxidants have been proven beneficial in the prevention or treatment of this sightthreatening condition in in vitro and in vivo experimental studies. This paper provides an overview of the pathogenesis of diabetic cataract, clinical studies investigating the association between diabetes and cataract development, and current treatment of cataract in diabetics.

Mechanism of Action and Safety of Second Generation Analogs of SDX-101 (R-Etodolac).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3411-3411 ◽  
Author(s):  
Lorenzo M. Leoni ◽  
Brian Crain ◽  
Brandi Bailey ◽  
Mimi Phillips ◽  
Heather Bendall ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Second Generation ◽  
Histopathological Examination ◽  
Clinical Signs ◽  
Lymphocytic Leukemia ◽  
Expression Vectors ◽  
Functional Assay ◽  
Ppar Γ

Abstract SDX-101 (R-etodolac), which is currently being evaluated in clinical trials for treatment of chronic lymphocytic leukemia, down regulates the activity of the β-catenin pathway and inhibits the growth of non-Hodgkin’s Lymphoma Daudi tumor xenografts in vivo when dosed orally (AACR PROC 2004 Abs# 2061 and #4574). Initial co-immunoprecipitation experiments conducted on cell nuclear fractions identified a heteromeric nuclear protein complex containing β-catenin and PPAR-γ. Furthermore, we have demonstrated that SDX-101 treatment reduces nuclear β-catenin in the immunoprecipitated complex, indicating that this complex may represent a target of SDX-101 (AACR PROC 2004 Abs# 3672). We recently reported evaluation of novel structural analogs of SDX-101 and have shown that these analogs, whose structures were not disclosed, are 5–10 fold more potent in in vitro cytotoxicity assays than SDX-101 and that they are orally efficacious in vivo (NCI/EORTC 2004 Abs #383). Our current studies further characterize the mechanism of action and safety of these analogs and identify the structures of selected analogs. Novel functional assays were developed to test and compare SDX-101 and the analogs at 4 hours post-treatment, a time before appreciable loss of viability was detected. Best results were obtained using a functional assay co-transfecting a β-catenin-dependent reporter construct (TOPFLASH) and β-catenin and RXR expression vectors. The average IC50 of analogs in this β-catenin reporter system ranged from 50 to 160 μM. These values were approximately five- to ten- fold lower than the IC50 for SDX-101 (~700 μM). Similar results were obtained assessing the inhibition of PPAR-γ-mediated transcription, using a PPAR-dependent reporter and co-transfection with PPAR-γ and RXR expression vectors. The average IC50s of the analogs ranged from 50–150 μM in this functional assay, demonstrating an approximately 10-fold increase in potency of the analogs when compared to SDX-101 (~1000 μM). No effect was observed at the 4 hour time point using a constitutive SV40-based control reporter vector. These results suggest that the primary target for these compounds may be a nuclear complex containing β-catenin, PPAR-γ and RXR, supporting a hypothesis developed upon evaluation of earlier results generated with SDX-101. To evaluate the safety of two SDX-101 analogs in vivo, normal mice were administered each analog at 240, 120 and 60 mg/kg/d (M-F) for four weeks. Mortality, morbidity, clinical signs, hematology/chemistry were monitored. There were no mortalities, overt toxicities or abnormal observations at necropsy with either of the analogs at any of the tested dose levels. There was a transient body weight loss (<5%) and a mild dose-independent increase in platelets and a reversible decrease in total bilirubin. Results of the histopathological examination of critical organs are pending. These results suggest, when given at doses previously shown to be efficacious in a DAUDI murine lymphoma model, these analogs were well tolerated. In conclusion, these data demonstrate that the second generation analogs of SDX-101 display more potent in vitro and in vivo activity while retaining a mechanism of action similar to that of SDX-101.

scholarly journals Antiviral activity of a novel mixture of natural antimicrobials, in vitro, and in a chicken infection model in vivo

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Igori Balta ◽  
Lavinia Stef ◽  
Ioan Pet ◽  
Patrick Ward ◽  
Todd Callaway ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Clinical Signs ◽  
Production Performance ◽  
Host Cells ◽  
Infection Model ◽  
Natural Antimicrobials ◽  
Infectious Bronchitis ◽  
Experimental Group

Abstract The aim of this study was to test in vitro the ability of a mixture of citrus extract, maltodextrin, sodium chloride, lactic acid and citric acid (AuraShield L) to inhibit the virulence of infectious bronchitis, Newcastle disease, avian influenza, porcine reproductive and respiratory syndrome (PRRS) and bovine coronavirus viruses. Secondly, in vivo, we have investigated its efficacy against infectious bronchitis using a broiler infection model. In vitro, these antimicrobials had expressed antiviral activity against all five viruses through all phases of the infection process of the host cells. In vivo, the antimicrobial mixture reduced the virus load in the tracheal and lung tissue and significantly reduced the clinical signs of infection and the mortality rate in the experimental group E2 receiving AuraShield L. All these effects were accompanied by a significant reduction in the levels of pro-inflammatory cytokines and an increase in IgA levels and short chain fatty acids (SCFAs) in both trachea and lungs. Our study demonstrated that mixtures of natural antimicrobials, such AuraShield L, can prevent in vitro viral infection of cell cultures. Secondly, in vivo, the efficiency of vaccination was improved by preventing secondary viral infections through a mechanism involving significant increases in SCFA production and increased IgA levels. As a consequence the clinical signs of secondary infections were significantly reduced resulting in recovered production performance and lower mortality rates in the experimental group E2.

scholarly journals Evaluating the Potential of Ursolic Acid as Bioproduct for Cutaneous and Visceral Leishmaniasis

Molecules ◽  
2020 ◽  
Vol 25 (6) ◽  
pp. 1394 ◽  
Author(s):  
Pablo Bilbao-Ramos ◽  
Dolores R. Serrano ◽  
Helga Karina Ruiz Saldaña ◽  
Juan J. Torrado ◽  
Francisco Bolás-Fernández ◽  
...  
Keyword(s):  
Ursolic Acid ◽  
Chronic Infection ◽  
Acute Infection ◽  
Parasite Burden ◽  
Immunological Response ◽  
Lesion Size ◽  
Experimental Models ◽  
Infection Model

Leishmaniasis affects around 12 million people worldwide and is estimated to cause the ninth-largest disease burden. There are three main forms of the disease, visceral (VL), cutaneous (CL), and mucocutaneous (MCL), leading to more than one million new cases every year and several thousand deaths. Current treatments based on chemically synthesized molecules are far from ideal. In this study, we have tested the in vitro and in vivo efficacy of ursolic acid (UA), a multifunctional triterpenoid with well-known antitumoral, antioxidant, and antimicrobial effects on different Leishmania strains. The in vitro antileishmanial activity against the intracellular forms was six and three-fold higher compared to extracellular forms of L. amazonensis and L. infantum, respectively. UA also showed to be a potent antileishmanial drug against both VL and CL manifestations of the disease in experimental models. UA parenterally administered at 5 mg/kg for seven days significantly reduced the parasite burden in liver and spleen not only in murine acute infection but also in a chronic-infection model against L. infantum. In addition, UA ointment (0.2%) topically administered for four weeks diminished (50%) lesion size progression in a chronic infection model of CL caused by L. amazonensis, which was much greater than the effect of UA formulated as an O/W emulsion. UA played a key role in the immunological response modulating the Th1 response. The exposure of Leishmania-infected macrophages to UA led to a significant different production in the cytokine levels depending on the Leishmania strain causing the infection. In conclusion, UA can be a promising therapy against both CL and VL.

scholarly journals Effect of Macrolide and Rifampin Resistance on Fitness of Rhodococcus equi during Intramacrophage Replication and In Vivo

2019 ◽  
Vol 87 (10) ◽  
Author(s):  
Jennifer M. Willingham-Lane ◽  
Londa J. Berghaus ◽  
Roy D. Berghaus ◽  
Kelsey A. Hart ◽  
Steeve Giguère
Keyword(s):  
Resistant Strain ◽  
Clinical Signs ◽  
Rhodococcus Equi ◽  
Infection Model ◽  
Content Type ◽  
Mouse Infection Model ◽  
Pulmonary Macrophages ◽  
Rifampin Resistance

ABSTRACT The soil-dwelling, saprophytic actinomycete Rhodococcus equi is a facultative intracellular pathogen of macrophages and causes severe bronchopneumonia when inhaled by susceptible foals. Standard treatment for R. equi disease is dual-antimicrobial therapy with a macrolide and rifampin. Thoracic ultrasonography and early treatment with antimicrobials prior to the development of clinical signs are used as means of controlling endemic R. equi infection on many farms. Concurrently with the increased use of macrolides and rifampin for chemoprophylaxis and the treatment of subclinically affected foals, a significant increase in the incidence of macrolide- and rifampin-resistant R. equi isolates has been documented. Previously, our laboratory demonstrated decreased fitness of R. equi strains that were resistant to macrolides, rifampin, or both, resulting in impaired in vitro growth in iron-restricted media and in soil. The objective of this study was to examine the effect of macrolide and/or rifampin resistance on intracellular replication of R. equi in equine pulmonary macrophages and in an in vivo mouse infection model in the presence and absence of antibiotics. In equine macrophages, the macrolide-resistant strain did not increase in bacterial numbers over time and the dual macrolide- and rifampin-resistant strain exhibited decreased proliferation compared to the susceptible isolate. In the mouse model, in the absence of antibiotics, the susceptible R. equi isolate outcompeted the macrolide- or rifampin-resistant strains.

scholarly journals Evaluation of the Efficacy of Doxycycline, Ciprofloxacin, Levofloxacin and Co-trimoxazole using in vitro and in vivo models of Q fever.

2021 ◽  
Author(s):  
K.A. Clay ◽  
M.G. Hartley ◽  
S. Armstrong ◽  
K.R. Bewley ◽  
K Godwin ◽  
...  
Keyword(s):  
Q Fever ◽  
Clinical Signs ◽  
Infection Model ◽  
Cell Infection ◽  
In Vivo Models ◽  
Recommended Treatment ◽  
Solid Media ◽  
Aerosol Infection

Q fever, caused by the intracellular pathogen Coxiella burnetii , is traditionally treated using tetracycline antibiotics, such as doxycycline. Doxycycline is often poorly tolerated and antibiotic resistant strains have been isolated. In this study, we have evaluated a panel of antibiotics (doxycycline, ciprofloxacin, levofloxacin, and, co-trimoxazole) against C. burnetii using in vitro methods (determination of MIC using liquid and solid media; efficacy assessment in a THP cell infection model) and in vivo methods (wax moth larvae and mouse models of infection). In addition, the schedule for antibiotic treatment has been evaluated, with therapy initiated at 24 h pre or post challenge. Both doxycycline and levofloxacin limited overt clinical signs during treatment in the AJ mouse model of aerosol infection, but further studies are required to investigate the possibility of disease relapse or incomplete bacterial clearance after the antibiotics are stopped. Levofloxacin was well tolerated and therefore warrants further investigation as an alternative to the current recommended treatment with doxycycline.

scholarly journals Antibacterial Mechanisms and Efficacy of Sarecycline in Animal Models of Infection and Inflammation

Antibiotics ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 439
Author(s):  
Christopher G. Bunick ◽  
Jonette Keri ◽  
S. Ken Tanaka ◽  
Nika Furey ◽  
Giovanni Damiani ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Bacterial Resistance ◽  
Antibiotic Use ◽  
In Vivo Studies ◽  
Infection Model ◽  
Severe Acne ◽  
Rat Paw Edema ◽  
Infection And Inflammation

Prolonged broad-spectrum antibiotic use is more likely to induce bacterial resistance and dysbiosis of skin and gut microflora. First and second-generation tetracycline-class antibiotics have similar broad-spectrum antibacterial activity. Targeted tetracycline-class antibiotics are needed to limit antimicrobial resistance and improve patient outcomes. Sarecycline is a narrow-spectrum, third-generation tetracycline-class antibiotic Food and Drug Administration (FDA)-approved for treating moderate-to-severe acne. In vitro studies demonstrated activity against clinically relevant Gram-positive bacteria but reduced activity against Gram-negative bacteria. Recent studies have provided insight into how the structure of sarecycline, with a unique C7 moiety, interacts with bacterial ribosomes to block translation and prevent antibiotic resistance. Sarecycline reduces Staphylococcus aureus DNA and protein synthesis with limited effects on RNA, lipid, and bacterial wall synthesis. In agreement with in vitro data, sarecycline demonstrated narrower-spectrum in vivo activity in murine models of infection, exhibiting activity against S. aureus, but reduced efficacy against Escherichia coli compared to doxycycline and minocycline. In a murine neutropenic thigh wound infection model, sarecycline was as effective as doxycycline against S. aureus. The anti-inflammatory activity of sarecycline was comparable to doxycycline and minocycline in a rat paw edema model. Here, we review the antibacterial mechanisms of sarecycline and report results of in vivo studies of infection and inflammation.

scholarly journals Development of a Fluorescent Tool for Studying Legionella bozemanae Intracellular Infection

2021 ◽  
Vol 9 (2) ◽  
pp. 379
Author(s):  
Breanne M. Head ◽  
Christopher I. Graham ◽  
Teassa MacMartin ◽  
Yoav Keynan ◽  
Ann Karen C. Brassinga
Keyword(s):  
Growth Kinetics ◽  
Legionella Pneumophila ◽  
Fluorescent Protein ◽  
Disease Incidence ◽  
Acanthamoeba Castellanii ◽  
Infection Model ◽  
Intracellular Infection ◽  
Green Fluorescent

Legionnaires’ disease incidence is on the rise, with the majority of cases attributed to the intracellular pathogen, Legionella pneumophila. Nominally a parasite of protozoa, L. pneumophila can also infect alveolar macrophages when bacteria-laden aerosols enter the lungs of immunocompromised individuals. L. pneumophila pathogenesis has been well characterized; however, little is known about the >25 different Legionella spp. that can cause disease in humans. Here, we report for the first time a study demonstrating the intracellular infection of an L. bozemanae clinical isolate using approaches previously established for L. pneumophila investigations. Specifically, we report on the modification and use of a green fluorescent protein (GFP)-expressing plasmid as a tool to monitor the L. bozemanae presence in the Acanthamoeba castellanii protozoan infection model. As comparative controls, L. pneumophila strains were also transformed with the GFP-expressing plasmid. In vitro and in vivo growth kinetics of the Legionella parental and GFP-expressing strains were conducted followed by confocal microscopy. Results suggest that the metabolic burden imposed by GFP expression did not impact cell viability, as growth kinetics were similar between the GFP-expressing Legionella spp. and their parental strains. This study demonstrates that the use of a GFP-expressing plasmid can serve as a viable approach for investigating Legionella non-pneumophila spp. in real time.

scholarly journals A Review on the Medicinal and Pharmacological Properties of Traditional Ethnomedicinal Plant Sonapatha, Oroxylum indicum

Sinusitis ◽  
2021 ◽  
Vol 5 (1) ◽  
pp. 71-89
Author(s):  
Ganesh Chandra Jagetia
Keyword(s):  
Glucose Transporter ◽  
Skin Diseases ◽  
Regulatory Element ◽  
Experimental Studies ◽  
Fatty Acid Synthetase ◽  
Preclinical Models ◽  
Oroxylin A ◽  
Oroxylum Indicum

Oroxylum indicum, Sonapatha is traditionally used to treat asthma, biliousness, bronchitis, diarrhea, dysentery, fevers, vomiting, inflammation, leukoderma, skin diseases, rheumatoid arthritis, wound injury, and deworm intestine. This review has been written by collecting the relevant information from published material on various ethnomedicinal and pharmacological aspects of Sonapatha by making an internet, PubMed, SciFinder, Science direct, and Google Scholar search. Various experimental studies have shown that Sonapatha scavenges different free radicals and possesses alkaloids, flavonoids, cardio glycosides, tannins, sterols, phenols, saponins, and other phytochemicals. Numerous active principles including oroxylin A, chrysin, scutellarin, baicalein, and many more have been isolated from the different parts of Sonapatha. Sonapatha acts against microbial infection, cancer, hepatic, gastrointestinal, cardiac, and diabetic disorders. It is useful in the treatment of obesity and wound healing in in vitro and in vivo preclinical models. Sonapatha elevates glutathione, glutathione-s-transferase, glutathione peroxidase, catalase, and superoxide dismutase levels and reduces aspartate transaminase alanine aminotransaminase, alkaline phosphatase, lactate dehydrogenase, and lipid peroxidation levels in various tissues. Sonapatha activates the expression of p53, pRb, Fas, FasL, IL-12, and caspases and inhibited nuclear factor kappa (NF-κB), cyclooxygenase (COX-2), tumor necrosis factor (TNFα), interleukin (IL6), P38 activated mitogen-activated protein kinases (MAPK), fatty acid synthetase (FAS), sterol regulatory element-binding proteins 1c (SREBP-1c), proliferator-activated receptor γ2 (PPARγ2), glucose transporter (GLUT4), leptin, and HPV18 oncoproteins E6 and E7 at the molecular level, which may be responsible for its medicinal properties. The phytoconstituents of Sonapatha including oroxylin A, chrysin, and baicalein inhibit the replication of SARS-CoV-2 (COVID-19) in in vitro and in vivo experimental models, indicating its potential to contain COVID-19 infection in humans. The experimental studies in various preclinical models validate the use of Sonapatha in ethnomedicine and Ayurveda.

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