scholarly journals Phage Therapy of Local and Systemic Disease Caused by Vibrio vulnificus in Iron-Dextran-Treated Mice

2002 ◽  
Vol 70 (11) ◽  
pp. 6251-6262 ◽  
Author(s):  
Karen E. Cerveny ◽  
Angelo DePaola ◽  
Donna H. Duckworth ◽  
Paul A. Gulig
Keyword(s):  
Phage Therapy ◽  
Vibrio Vulnificus ◽  
Therapeutic Potential ◽  
Systemic Disease ◽  
Lethal Dose ◽  
Rapid Progression ◽  
Iron Dextran ◽  
Histopathologic Analysis ◽  
Systemic Infections

ABSTRACT Vibrio vulnificus is a gram-negative bacterium that contaminates filter-feeding shellfish such as oysters. After ingestion of contaminated oysters, predisposed people may experience highly lethal septicemia. Contamination of wounds with the bacteria can result in devastating necrotizing fasciitis, which can progress to septicemia. The extremely rapid progression of these diseases can render antibiotic treatment ineffective, and death is a frequent outcome. In this study, we examined the potential use of bacteriophages as therapeutic agents against V. vulnificus in an iron-dextran-treated mouse model of V. vulnificus infection. Mice were injected subcutaneously with 10 times the lethal dose of V. vulnificus and injected intravenously, either simultaneously or at various times after infection, with phages. Treatment of mice with phages could prevent death; systemic disease, as measured by CFU per gram of liver and body temperature; and local disease, as measured by CFU per gram of lesion material and histopathologic analysis. Two different phages were effective against three different V. vulnificus strains with various degrees of virulence, while a third phage that required the presence of seawater to lyse bacteria in vitro was ineffective at treating mice. Optimum protection required that the phages be administered within 3 h of bacterial inoculation at doses as high as 108 PFU. One of the protective phages had a half-life in blood of over 2 h. These results demonstrate that bacteriophages have therapeutic potential for both localized and systemic infections caused by V. vulnificus in animals. This model should be useful in answering basic questions regarding phage therapy.

scholarly journals lncRNA Chronos is an aging-induced inhibitor of muscle hypertrophy

2017 ◽  
Vol 216 (11) ◽  
pp. 3497-3507 ◽  
Author(s):  
Ronald L Neppl ◽  
Chia-Ling Wu ◽  
Kenneth Walsh
Keyword(s):  
Skeletal Muscle ◽  
Noncoding Rna ◽  
Muscle Hypertrophy ◽  
Systemic Disease ◽  
Noncoding Rnas ◽  
Rapid Progression ◽  
Gradual Loss ◽  
Epigenetic Modulation

Skeletal muscle exhibits remarkable plasticity in its ability to modulate its mass in response to the physiologic changes associated with functional use, systemic disease, and aging. Although a gradual loss of muscle mass normally occurs with advancing age, its increasingly rapid progression results in sarcopenia in a subset of individuals. The identities of muscle-enriched, long noncoding RNAs that regulate this process are unknown. Here, we identify a long noncoding RNA, named Chronos, whose expression in muscle is positively regulated with advancing age and negatively regulated during Akt1-mediated growth. Inhibition of Chronos induces myofiber hypertrophy both in vitro and in vivo, in part, through the epigenetic modulation of Bmp7 signaling.

scholarly journals Bactericidal Effects of Toluidine Blue-Mediated Photodynamic Action on Vibrio vulnificus

2005 ◽  
Vol 49 (3) ◽  
pp. 895-902 ◽  
Author(s):  
Tak-Wah Wong ◽  
Yin-Yi Wang ◽  
Hamm-Ming Sheu ◽  
Yin-Ching Chuang
Keyword(s):  
Toluidine Blue ◽  
Vibrio Vulnificus ◽  
Opportunistic Infections ◽  
Red Light ◽  
Lethal Dose ◽  
Wound Infections ◽  
Bactericidal Effects ◽  
Lower Light ◽  
Photodynamic Reaction

ABSTRACT Vibrio vulnificus is a gram-negative, highly invasive bacterium responsible for human opportunistic infections. We studied the antibacterial effects of toluidine blue O (TBO)-mediated photodynamic therapy (PDT) for V. vulnificus wound infections in mice. Fifty-three percent (10 of 19) of mice treated with 100 μg of TBO per ml and exposed to broad-spectrum red light (150 J/cm2 at 80 mW/cm2) survived, even though systemic septicemia had been established with a bacterial inoculum 100 times the 50% lethal dose. In vitro, the bacteria were killed after exposure to a lower light dose (100 J/cm2 at 80 mW/cm2) in the presence of low-dose TBO (0.1 μg/ml). PDT severely damaged the cell wall and reduced cell motility and virulence. Cell-killing effects were dependent on the TBO concentration and light doses and were mediated partly through the reactive oxygen species generated during the photodynamic reaction. Our study has demonstrated that PDT can cure mice with otherwise fatal V. vulnificus wound infections. These promising results suggest the potential of this regimen as a possible alternative to antibiotics in future clinical applications.

scholarly journals Phytochemical profile, toxicological evaluation of Rhipsalis baccifera (Sol.) Stearn (Cactaceae) extract and their antitumor activity in Ehrlich carcinoma-bearing mice

2021 ◽  
Author(s):  
Jéssica Alves Cavalcantea ◽  
Luiz da Silva Maia Neto ◽  
Anna Lígia de Castro Figueiredo ◽  
Weslley Oliveira ◽  
José Roberto Pimentel Cabral de Seixas ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Therapeutic Potential ◽  
Lethal Dose ◽  
Artemia Salina ◽  
Subsequent Treatment ◽  
Ehrlich Carcinoma ◽  
Toxicological Evaluation ◽  
Phytochemical Profile

<i>Rhipsalis baccifera</i> (Sol.) Stearn is a typical cactus from tropical regions with wide geographic distribution, and its therapeutic potential is not yet fully understood, such as antitumoral property. Thus, this study evaluated the cytotoxic ethanolic extract of <i>R. baccifera</i> (EERB) and its antitumor activity against Erlich's tumor in mice. The EERB was obtained, and its phytochemical profile was filed by thin-layer chromatography. The toxicity was evaluated in vitro and in vivo using the microcrustacean<i> Artemia salina</i> Leach and mice. The lethal dose was determined after implantation of a tumor cell suspension, with subsequent treatment with EERB (200 mg/kg and 100 mg/kg) 48h after implantation. These values represent the tenth part of the DL<sub>50</sub> and CL<sub>50</sub>, respectively. The presence of phenols, tannins and triterpenes were demonstrated in the phytochemical results. Toxicity was dose-dependent, and the tumor inhibition was 84.1% and 75.8% at doses of 200 mg/kg and 100 mg/kg, respectively. We can highlight that the growth of Erlich's carcinoma suffered inhibitory effects against the EERB. EERB was found to have low acute toxicity and a high potential for use in antitumor therapy. Thus, new studies involving pre-clinical and clinical analyses of the extract are essential to determine the safe dose.

scholarly journals Genomic, Morphological and Functional Characterization of Virulent Bacteriophage IME-JL8 Targeting Citrobacter freundii

2020 ◽  
Vol 11 ◽  
Author(s):  
Kaixiang Jia ◽  
Nuo Yang ◽  
Xiuwen Zhang ◽  
Ruopeng Cai ◽  
Yang Zhang ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Phage Therapy ◽  
Genomic Sequence ◽  
Functional Characterization ◽  
Lethal Dose ◽  
Citrobacter Freundii ◽  
Alternative Treatment Strategy ◽  
Ph Range

Citrobacter freundii refers to a fish pathogen extensively reported to be able to cause injury and high mortality. Phage therapy is considered a process to alternatively control bacterial infections and contaminations. In the present study, the isolation of a virulent bacteriophage IME-JL8 isolated from sewage was presented, and such bacteriophage was characterized to be able to infect Citrobacter freundii specifically. Phage IME-JL8 has been classified as the member of the Siphoviridae family, which exhibits the latent period of 30–40 min. The pH and thermal stability of phage IME-JL8 demonstrated that this bacteriophage achieved a pH range of 4–10 as well as a temperature range of 4, 25, and 37°C. As revealed from the results of whole genomic sequence analysis, IME-JL8 covers a double-stranded genome of 49,838 bp (exhibiting 47.96% G+C content), with 80 putative coding sequences contained. No bacterial virulence- or lysogenesis-related ORF was identified in the IME-JL8 genome, so it could be applicable to phage therapy. As indicated by the in vitro experiments, phage IME-JL8 is capable of effectively removing bacteria (the colony count decreased by 6.8 log units at 20 min), and biofilm can be formed in 24 h. According to the in vivo experiments, administrating IME-JL8 (1 × 107 PFU) was demonstrated to effectively protect the fish exhibiting a double median lethal dose (2 × 109 CFU/carp). Moreover, the phage treatment led to the decline of pro-inflammatory cytokines in carp with lethal infections. IME-JL8 was reported to induce efficient lysis of Citrobacter freundii both in vitro and in vivo, thereby demonstrating its potential as an alternative treatment strategy for infections attributed to Citrobacter freundii.

scholarly journals Characterization and Pathogenic Significance of Vibrio vulnificus Antigens Preferentially Expressed in Septicemic Patients

2003 ◽  
Vol 71 (10) ◽  
pp. 5461-5471 ◽  
Author(s):  
Young Ran Kim ◽  
Shee Eun Lee ◽  
Choon Mee Kim ◽  
Soo Young Kim ◽  
Eun Kyoung Shin ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Transcriptional Activation ◽  
Pathogenic Bacteria ◽  
Virulence Genes ◽  
Vibrio Vulnificus ◽  
Lethal Dose ◽  
Hypothetical Protein ◽  
Expression Library

ABSTRACT Many important virulence genes of pathogenic bacteria are preferentially expressed in vivo. We used the recently developed in vivo-induced antigen technology (IVIAT) to identify Vibrio vulnificus genes induced in vivo. An expression library of V. vulnificus was screened by colony blot analysis by using pooled convalescent-phase serum that had been thoroughly adsorbed with in vitro-expressed V. vulnificus whole cells and lysates. Twelve clones were selected, and the sequences of the insert DNAs were analyzed. The DNA sequences showed homologies with genes encoding proteins of diverse functions: these functions included chemotaxis (a methyl-accepting chemotaxis protein), signaling (a GGDEF-containing protein and a putative serine/threonine kinase), biosynthesis and metabolism (PyrH, PurH, and IlvC), secretion (TatB and plasmid Achromobacter secretion [PAS] factor), transcriptional activation (IlvY and HlyU), and the activity of a putative lipoprotein (YaeC). In addition, one identified open reading frame encoded a hypothetical protein. Isogenic mutants of the 12 in vivo-expressed (ive) genes were constructed and tested for cytotoxicity. Cytotoxic activity of the mutant strains, as measured by lactate dehydrogenase release from HeLa cells, was nearly abolished in pyrH, purH, and hlyU mutants. The intraperitoneal 50% lethal dose in mice increased by ca. 10- to 50-fold in these three mutants. PyrH and PurH seem to be essential for in vivo growth. HlyU appears to be one of the master regulators of in vivo virulence expression. The successful identification of ive genes responsible for the in vivo bacterial virulence, as done in the present study, demonstrates the usefulness of IVIAT for the detection of new virulence genes.

Bcl-XL down-regulation suppresses the tumorigenic potential of NPM/ALK in vitro and in vivo

Blood ◽  
2004 ◽  
Vol 103 (7) ◽  
pp. 2787-2794 ◽  
Author(s):  
Addolorata Maria Luce Coluccia ◽  
Silvia Perego ◽  
Loredana Cleris ◽  
Rosalind Helen Gunby ◽  
Lorena Passoni ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Systemic Disease ◽  
Large Cell ◽  
Common Finding ◽  
Down Regulation ◽  
Anaplastic Lymphoma ◽  
Mitochondrial Homeostasis ◽  
Tumorigenic Potential

Abstract Deregulated apoptosis is a common finding in tumorigenesis. The oncogenic tyrosine kinase nucleophosmin/anaplastic lymphoma kinase (NPM/ALK) delivers a strong survival signal in anaplastic large cell lymphomas (ALCLs). Although NPM/ALK activates multiple antiapoptotic pathways, the biologic relevance and therapeutic potential of more downstream apoptotic effectors are mostly unknown. In this report, the NPM/ALK-mediated induction of Bcl-XL (but not of Bcl-2) was identified in human ALCL-derived cells. NPM/ALK kinase activity was required to promote Bcl-XL expression and its protective effect on mitochondrial homeostasis. Down-regulation of Bcl-XL significantly reduced the antiapoptotic potential of NPM/ALK in both transformed murine Ba/F3 pro-B cells and human ALCL-derived KARPAS-299 cells. To elucidate the role of Bcl-XL in vivo, Ba/F3-NPM/ALK+ cells expressing a doxycycline (Dox)-inducible Bcl-XL antisense transgene (pTet-ON) were injected into nude mice. Doxycycline administration prevented a fatal systemic disease in 15 of 15 intravenously injected mice and the appearance of subcutaneous tumor xenografts in 9 of 12 mice; in vivo down-regulation of Bcl-XL was also documented. Our results show a pivotal role for Bcl-XL in ALK-mediated oncogenicity; a single protein placed downstream of a known oncogene can be crucial for the survival of neoplastic cells both in vitro and in vivo. Bcl-XL deserves further investigation as a possible therapeutic target in ALK+ ALCLs. (Blood. 2004;103:2787-2794)

scholarly journals Pathogenesis of Infection by Clinical and Environmental Strains of Vibrio vulnificus in Iron-Dextran-Treated Mice

2000 ◽  
Vol 68 (10) ◽  
pp. 5785-5793 ◽  
Author(s):  
Angela M. Starks ◽  
Trenton R. Schoeb ◽  
Mark L. Tamplin ◽  
Salina Parveen ◽  
Thomas J. Doyle ◽  
...  
Keyword(s):  
Vibrio Vulnificus ◽  
Systemic Disease ◽  
Disease Process ◽  
Systemic Infection ◽  
Opportunistic Pathogen ◽  
Skin Lesions ◽  
Host Cells ◽  
Iron Dextran ◽  
Lethal Doses ◽  
Host Tissues

ABSTRACT Vibrio vulnificus is an opportunistic pathogen that contaminates oysters harvested from the Gulf of Mexico. In humans with compromising conditions, especially excess levels of iron in plasma and tissues, consumption of contaminated seafood or exposure of wounds to contaminated water can lead to systemic infection and disfiguring skin infection with extremely high mortality. V. vulnificus-associated diseases are noted for the rapid replication of the bacteria in host tissues, with extensive tissue damage. In this study we examined the virulence attributes of three virulent clinical strains and three attenuated oyster or seawater isolates in mouse models of systemic disease. All six V. vulnificus strains caused identical skin lesions in subcutaneously (s.c.) inoculated iron dextran-treated mice in terms of numbers of recovered CFU and histopathology; however, the inocula required for identical frequency and magnitude of infection were at least 350-fold higher for the environmental strains. At lethal doses, all strains caused s.c. skin lesions with extensive edema, necrosis of proximate host cells, vasodilation, and as many as 108CFU/g, especially in perivascular regions. These data suggest that the differences between these clinical and environmental strains may be related to growth in the host or susceptibility to host defenses. In non-iron dextran-treated mice, strains required 105-fold-higher inocula to cause an identical disease process as with iron dextran treatment. These results demonstrate that s.c. inoculation of iron dextran-treated mice is a useful model for studying systemic disease caused by V. vulnificus.

scholarly journals Ibrexafungerp, a Novel Oral Triterpenoid Antifungal in Development: Overview of Antifungal Activity Against Candida glabrata

2021 ◽  
Vol 11 ◽  
Author(s):  
Ahmed Gamal ◽  
Sherman Chu ◽  
Thomas S. McCormick ◽  
Katyna Borroto-Esoda ◽  
David Angulo ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Systemic Disease ◽  
Wild Type ◽  
First Line ◽  
Life Threatening ◽  
Oral Availability ◽  
Synthase Inhibitor ◽  
Preclinical And Clinical Studies ◽  
Systemic Infections

Systemic infections caused by Candida species are an important cause of morbidity and mortality among immunocompromised and non-immunocompromised patients. In particular, Candida glabrata is an emerging species within the Candida family that causes infections ranging from superficial to life-threatening systemic disease. Echinocandins and azoles are typically the first-line therapies used to treat infections caused by C. glabrata, however, there is an increasing prevalence of resistance to these antifungal agents in patients. Thus, a need exists for novel therapies that demonstrate high efficacy against C. glabrata. Ibrexafungerp is a first-in-class glucan synthase inhibitor with oral availability developed to address this increasing antifungal resistance. Ibrexafungerp demonstrates broad in vitro activity against wild-type, azole-resistant, and echinocandin-resistant C. glabrata species. Furthermore, ibrexafungerp has shown efficacy in low pH environments, which suggests its potential effectiveness in treating vulvovaginal candidiasis. Additional preclinical and clinical studies are needed to further examine the mechanism(s) of ibrexafungerp, including acting as a promising new agent for treating C. glabrata infections.

High Level Expression and Purification of King Cobra Cathelicidin OH-CATH30 in Escherichia coli as a Thioredoxin Fusion Protein

2014 ◽  
Vol 926-930 ◽  
pp. 997-1000
Author(s):  
Tong Yi Sun
Keyword(s):  
Escherichia Coli ◽  
Fusion Protein ◽  
Therapeutic Potential ◽  
Expression System ◽  
Expression And Purification ◽  
High Level Expression ◽  
High Level ◽  
Systemic Infections ◽  
King Cobra

The Cathelicidin OH-CATH30 may have therapeutic potential against the systemic infections. However, it is a great challenge to obtain abundant OH-CATH30 by Escherichia coli expression system. The OH-CATH30 coding sequence was optimized and subcloned into vector pET-32a, allowing the peptide to be expressed as a thioredoxin fusion protein. The highest protein expression level obtained was 100 mg/L of bacterial culture. Before being cleaved with enterokinase, the released recombinant OH-CATH30 exhibited a in vitro strong antibacterial activity against the control strains.

scholarly journals Therapy of Experimental Pseudomonas Infections with a Nonreplicating Genetically Modified Phage

2004 ◽  
Vol 48 (10) ◽  
pp. 3817-3822 ◽  
Author(s):  
Steven Hagens ◽  
André Habel ◽  
Uwe von Ahsen ◽  
Alexander von Gabain ◽  
Udo Bläsi
Keyword(s):  
Survival Rate ◽  
Bacterial Infections ◽  
Phage Therapy ◽  
Lethal Dose ◽  
Survival Rates ◽  
Genetically Engineered ◽  
Lytic Phage ◽  
Bacteriophage Therapy ◽  
Genes Encoding

ABSTRACT Bacteriophage therapy of bacterial infections has received renewed attention owing to the increasing prevalence of antibiotic-resistant pathogens. A side effect of many antibiotics as well as of phage therapy with lytic phage is the release of cell wall components, e.g., endotoxins of gram-negative bacteria, which mediate the general pathological aspects of septicemia. Here we explored an alternative strategy by using genetically engineered nonreplicating, nonlytic phage to combat an experimental Pseudomonas aeruginosa infection. An export protein gene of the P. aeruginosa filamentous phage Pf3 was replaced with a restriction endonuclease gene. This rendered the Pf3 variant (Pf3R) nonreplicative and concomitantly prevented the release of the therapeutic agent from the target cell. The Pf3R phage efficiently killed a wild-type host in vitro, while endotoxin release was kept to a minimum. Treatment of P. aeruginosa infections of mice with Pf3R or with a replicating lytic phage resulted in comparable survival rates upon challenge with a minimal lethal dose of 3. However, the survival rate after phage therapy with Pf3R was significantly higher than that with the lytic phage upon challenge with a minimal lethal dose of 5. This higher survival rate correlated with a reduced inflammatory response elicited by Pf3R treatment relative to that with the lytic phage. Therefore, this study suggests that the increased survival rate of Pf3R-treated mice could result from reduced endotoxin release. Thus, the use of a nonreplicating modified phage for the delivery of genes encoding proteins toxic to bacterial pathogens may open up a new avenue in antimicrobial therapy.

Sign in / Sign up

Export Citation Format

Share Document