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Effect of Oral Administration of Methylene Blue MMX Tablets on Double Stranded DNA

ABSTRACT: Single Centre, open label assignment phase II clinical study. To evaluate the effect of oral 200mg Methylene Blue tablets (administered 8x25mg) prior to endoscopy on double stranded DNA breaks in colonic biopsy samples assessed by histone gamma H2AX analysis, compared to control biopsies.

DISEASE(S): Colonoscopy,Out-patients Of Both Sexes Scheduled For A Screening Or Surveillance Colonoscopy And Identified As Having The Clinical Requirement For A Second Colonoscopy Within 2 Weeks Of The Initial Colonoscopy.,Pazienti Ambulatoriali Di Entrambi I Sessi Con Indicazione Ad Effettuare Una Coloscopia E Che Alla Coloscopia Presentino Caratteristiche Endoscopiche E Cliniche Tali Da Richiedere Di Procedere, Entro 2 Settimane, Ad Una Seconda Coloscopia.,Colorectal Cancer,Colorectal Neoplasms

PROVIDER: 2178654 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Background: Cerebral ischemia/reperfusion injury is a common secondary effect of cardiac arrest which is largely responsible for postresuscitative mortality. Therefore development of therapies which restore and protect the brain function after cardiac arrest is essential. Methylene blue (MB) has been experimentally proven neuroprotective in a porcine model of global ischemia-reperfusion in experimental cardiac arrest. However, no comprehensive analyses have been conducted at gene expression level. Methods: Pigs underwent either untreated cardiac arrest (CA) or CA with subsequent cardiopulmonary resuscitation (CPR) accompanied with an infusion of saline or an infusion of saline with MB. Genome-wide transcriptional profiling using the Affymetrix porcine microarray was performed to 1) gain understanding of delayed neuronal death initiation in porcine brain during ischemia and after 30, 60 and 180 min following reperfusion, and 2) identify the mechanisms behind the neuroprotective effect of MB after ischemic injury (at 30, 60 and 180 min). Results: Our results show that restoration of spontaneous circulation (ROSC) induces major transcriptional changes related to stress response, inflammation, apoptosis and even cytoprotection. In contrast, the untreated ischemic and anoxic insult affected only few genes mainly involved in intra-/extracellular ionic balance. Furthermore, our data show that the neuroprotective role of MB is diverse and fulfilled by regulation of the expression of soluble guanylate cyclase and biological processes accountable for inhibition of apoptosis, modulation of stress response, neurogenesis and neuroprotection. Conclusions: Our results support that MB could be a valuable intervention and should be investigated as a therapeutic agent against neural damage associated with I/R injury induced by cardiac arrest. One group of pigs underwent cardiac arrest (CA) without subsequent cardiopulmonary resuscitation (CPR) and the brain of the animals was removed after 5, 20 or 30 min post CA for genome-wide expression study. Two groups of pigs underwent first CA for 12 min with a subsequent 8 min-long CPR and received either an infusion of saline or an infusion of saline with MB from one minute after the start of CPR until 50 min after return of spontaneous circulation (ROSC). In both latter groups the brains were removed for microarray analysis at the following time points: 30, 60, 180 min.

Project description:A promising alternative to antibiotics for treatment of Staphylococcus aureus infections is photodynamic inactivation (PDI), which employs a photosensitizer (PS) that produces cytotoxic reactive oxygen species (ROS) when exposed to molecular oxygen and antimicrobial blue light in the spectrum of 400-470 nm. Although the precise mechanistic basis of PDI has not been defined, the formation of ROS and free radicals that oxidize a number of cellular targets, including membrane lipids, damage to proteins and nucleic acids result in inactivation of essential cellular functions and subsequent cell death. Because PDI is non-selective and affects multiple cellular targets, development of resistance or tolerance to PDI has been considered to be unlikely and attempts to induce S. aureus resistance or tolerance upon repeated sub-lethal doses of PDI have not succeeded. However, multiple aspects of PDI suggest that development of tolerance is highly probable, in particular when PDI is used for treatment of infections where the environment at the infection site prevents penetration of PDI at a level sufficient to cause death of all bacteria and with tolerant phenotypes emerging from the surviving bacteria. In this study, we sought to identify the mechanisms that contribute to PDI tolerance in S. aureus. S. aureus HG003 and the isogenic HG003DmutSL strain with defects in DNA mismatch repair were used to evaluate the response of S. aureus and the roles of DNA mismatch repair and gene regulatory networks to repeated sublethal doses of PDI. Global transcriptome and genome analyses were used in an agnostic approach to identify the underlying transcriptional responses and genetic adaptations that occur as a result of repeated PDI and contribute to PDI tolerance. Our results reveal multiple metabolic, transport and cell wall biogenesis pathways that contribute to PDI tolerance, and a S. aureus regulatory gene likely responsible for the adaptive transcriptional response to PDI.

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Effect of Oral Administration of Methylene Blue MMX Tablets on Double Stranded DNA

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