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Radiation-induced gastrointestinal injury (RIGI) is a serious side effect of abdominal and pelvic radiotherapy, which often limits the treatment of gastrointestinal and gynaecological cancers. RIGI is also observed during accidental radiological or nuclear scenarios with no approved agents available till date to prevent or mitigate RIGI in humans. Trichostatin A (TSA), an epigenetic modulator, has been currently in clinical trials for cancer treatment and is also well known for its antibiotic and antifungal properties. In this study, partial body (abdominal) irradiation mice model was used to investigate the mitigative effect of TSA against gastrointestinal toxicity caused by gamma radiation. Mice were checked for alterations in mean body weight, diarrheal incidence, disease activity index and survival against 15 Gy radiation. Structural abnormalities in intestine and changes in microbiota composition were studied by histopathology and 16S rRNA sequencing of fecal samples respectively. Immunoblotting and biochemical assays were performed to check protein nitrosylation, expression of inflammatory mediators, infiltration of inflammatory cells and changes in pro-inflammatory cytokine. TSA administration to C57Bl/6 mice improved radiation induced mean body weight loss, maintained better health score, reduced disease activity index and promoted survival. The 16S rRNA sequencing of fecal DNA demonstrated that TSA influenced the fecal microbiota dynamics with significant alterations in the Firmicutes/Bacteriodetes ratio. TSA effectively mitigated intestinal injury, down-regulated NF-κB, Cox-2, iNOS expression, inhibited PGE2 and protein nitrosylation levels in irradiated intestine. The upregulation of NLRP3-inflammasome complex and infiltrations of inflammatory cells in the inflamed intestine were also prevented by TSA. Subsequently, the myeloperoxidase activity in intestine alongwith serum IL-18 levels was found reduced. These findings provide evidence that TSA inhibits inflammatory mediators, alleviates gut dysbiosis, and promotes structural restoration of the irradiated intestine. TSA, therefore, can be considered as a potential agent for mitigation of RIGI in humans. Depicting the possible mechanism of action of TSA against radiation induced gastrointestinal injury in mice. Radiation leads to activation of NF-κB, the master regulator of inflammation and it target proteins Cox-2 and iNOS. Activation of these key inflammatory mediators further up-regulated NLRP3/inflammosome complex, NO-mediated protein modifications and infiltration of inflammatory cells in the irradiated intestine. Further alterations in diversity and composition of gut microbiota contributed to inflammation and GI injury in presence of radiation. TSA administration post irradiation maintained intestinal integrity, and reduced inflammation. Restoration of gut microbiota dynamics and reduced inflammation by TSA might have mitigated radiation mediated gastrointestinal injury and have contributed to survival against irradiation. [ABSTRACT FROM AUTHOR]

Trichostatin A (TSA) has been shown to mitigate whole body γ-radiation-induced morbidity and mortality. The current study aimed at studying the effects of TSA post-irradiation treatment on gut-microbiota, especially the translocation of the microbes from the intestine to other organs in C57 Bl/6 mice model. On 1st, 3rd 5th 7th 9th 12th and 14th days after various treatments bacteria were isolated from the intestine and nearby organs (mesenteric lymph node, spleen and liver) for further analysis. The jejunum part of all animals was processed for histological analysis. The group radiation + drug showed reduced susceptibility to radiation injury as well as microbiota related anomalies compared to the irradiated alone group. This was described by increased microflora in different parts of the GI tract in the radiation + drug group compared to the irradiated group and reduced histopathological damages in the jejunum. Also, a reduced percentage of translocated bacteria were found in different organs of radiation + drug group animals. TSA treatment post-irradiation could effectively control bacterial translocation as well as GI injury in mice. [ABSTRACT FROM AUTHOR]

Purpose: Ionizing radiation is known to damage male reproductive system. Current study aims to study the mitigative effects of trichostatin A on male reproductive system and accompanying metabolite changes in testicular tissue of mice. Materials and methods: Eight-week-old male C57 Bl/6J mice were exposed to 2 Gy γ-radiation with or without trichostatin A administration. The animals were sacrificed at various time intervals for organ body weight index, sperm head abnormality assay, sperm mobility assay, and study of various metabolites in testicular tissue using NMR spectroscopy. Results: Ionizing radiation induced no significant change in organ body weight index at any time points studied, however a significant increase in sperm head abnormality and significant decrease in sperm mobility was evident on fifth postirradiation week. trichostatin A administration, 1 and 24 h postirradiation, could efficiently mitigate radiation-induced changes studied. NMR metabolome profile also showed prominent changes associated with energy metabolism, osmolytes and membrane metabolism at 24 h postirradiation and some of these changes (choline, glycerolphosphoethanol amine, and glycine) were persistent till fifth postirradiation week. Trichostatin A administration resulted in reverting metabolic profile of the irradiated animals to normal level suggesting its mitigative role. Conclusion: Results obtained suggest that trichostatin A could restore normal metabolic profile of testicular tissue of irradiated male mice and also restored certain morphological and functional properties of sperms. Trichostatin A thus could further be exploited for its radio-mitigative properties. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the severity of damage induced in plasmid DNA by ultrasoft X-rays at different energies, in order to unravel the correlation between the sharp increase in cell-killing efficiency of ultrasoft X-rays above versus below the carbon K-threshold and the induction of core events in DNA atoms. Materials and methods: Bluescript (pBS, tight packing) and pSP189 (pSP, loose packing) plasmids were exposed to ultrasoft X-rays at 250, 380 and 760 eV energies, respectively, above phosphorus L-, carbon K- and oxygen K-thresholds. Complex DNA lesions were assayed by the repair protein Formamidopyrimidine DNA glycosylase (Fpg) and by in vitro repair assay using whole cell-free extracts. Results: Clustered damage, as revealed by Fpg-induced double strand breaks, was observed at low level, but at similar rate at the three energies. Damage induced at 380 eV may be slightly less efficiently repaired by cell extracts than those produced at 250 eV. 760 eV photons which yield longer range electrons than 250 and 380 eV photons, induced more total damages which were more efficiently repaired, and thus likely more dispersed. Conclusion: It is demonstrated that ultrasoft X-rays induce complex damage, which do not exhibit the same ability to be repaired, depending on the energy and on DNA packing. [ABSTRACT FROM AUTHOR]

AbstractIntravenous and oral 14 d repeated dose toxicity studies of Trichostatin A (TSA) were carried out in Swiss albino mice using low, intermediate, and high doses. Intravenous doses were 10, 25, and 50 μg/kg b.w while the oral doses were 20, 50, and 100 μg/kg b.w. Respective control groups of mice were administered phosphate buffered saline (vehicle only) for 14 consecutive days. All external morphological, hematological, biochemical, urine, histopathological, food intake in addition to body weight and vital organ weight were recorded. During the study no mortality in any animal was observed in either treatment routes. There were no significant changes in morphology, food intake, hematology, biochemical, urine analysis, organ weight. Animals treated high dose of TSA intravenously (50 μg/kg b.w) and orally (100 μg/kg b.w) had enlarged, congested, and discolored kidneys which were statistically significant. Histopathological studies had shown statistically significant degenerated glomerulus in high dose of intravenous and orally treated animals and degenerated tubule were found in orally treated animals. Genotoxicity was evaluated using micronucleus frequency at 14 and 21 d after treatment and chromosomal aberration at 21 d after treatment. Micronucleaus assay and chromosomal assay however did not show any significant changes at any doses and administration routes. Therefore, this study concludes that dose ∼25 µg/kg and ∼50 µg/kg b.w may be considered as No Observed Adverse Effect Level (NOAEL) for intravenous and oral administration of TSA respectively. [ABSTRACT FROM AUTHOR]