Radiation damage can cause a series of gastrointestinal(GI)tract diseases.The development of safe and effective GI tract radioprotectants still remains a great challenge clinically.Here,we firstly report an oral radioprotectant Gel@GYY that integrates a porous gelatin-based(Gel)hydrogel and a pH-responsive hydrogen sulfide(H2S)donor GYY4137(morpholin-4-ium 4 methoxyphenyl(morpholino)phosphinodithioate).Gel@GYY has a remarkable adhesion ability and long retention time,which not only enables responsive release of low-dose H2S in stomach and subsequently sustained release of H2S in the whole intestinal tract especially in the colon,but also ensures a close contact between H2S and GI tract.The released H2S can effectively scavenge free radicals induced by X-ray radiation,reduce lipid peroxidation level,repair DNA damage and recover vital superoxide dismutase and glutathione peroxidase activities.Meanwhile,the released H2S inhibits radiation-induced activation of nuclear factorκB(NF-κB),thus reducing inflammatory cytokines levels in GI tract.After treatment,Gel@GYY displays efficient excretion from mice body due to its biodegradability.This work provides a new insight for therapeutic application of intelligent H2S-releasing oral delivery system and potential alternative to clinical GI physical damage protectant.
BACKGROUND Human Wharton’s jelly-derived mesenchymal stromal/stem cells(hWJ-MSCs)have gained considerable attention in their applications in cell-based therapy due to several advantages offered by them.Recently,we reported that hWJ-MSCs and their conditioned medium have significant therapeutic radioprotective potential.This finding raised an obvious question to identify unique features of hWJ-MSCs over other sources of stem cells for a better understanding of its radioprotective mechanism.AIM To understand the radioprotective mechanism of soluble factors secreted by hWJMSCs and identification of their unique genes.METHODS Propidium iodide staining,endogenous spleen colony-forming assay,and survival study were carried out for radioprotection studies.Homeostasis-driven proliferation assay was performed for in vivo lymphocyte proliferation.Analysis of RNAseq data was performed to find the unique genes of WJ-MSCs by comparing them with bone marrow mesenchymal stem cells,embryonic stem cells,and human fibroblasts.Gene enrichment analysis and protein-protein interaction network were used for pathway analysis.RESULTS Co-culture of irradiated murine splenic lymphocytes with WJ-MSCs offered significant radioprotection to lymphocytes.WJ-MSC transplantation increased the homeostasis-driven proliferation of the lymphocytes.Neutralization of WJ-MSC conditioned medium with granulocyte-colony stimulating factor antibody abolished therapeutic radioprotection.Transcriptome analysis showed that WJ-MSCs share several common genes with bone marrow MSCs and embryonic stem cells and express high levels of unique genes such as interleukin(IL)1-α,IL1-β,IL-6,CXCL3,CXCL5,CXCL8,CXCL2,CCL2,FLT-1,and IL-33.It was also observed that WJ-MSCs preferentially modulate several cellular pathways and processes that handle the repair and regeneration of damaged tissues compared to stem cells from other sources.Cytokine-based network analysis showed that most of the radiosensitive tissues have a more complex network for the elevated cytokines.CONC
Objective:To investigate patient-specific radioprotection mathods for people in close contact with cancer patientstreated by 12I-seed implantation.Methods:The initial dose rates(D_(0))at distances of 30 and 100 cm from 80 patients who had undergone ^(125)I-seed implantation were measured within 24 h of the procedure.The dose rate at t(D_(t))and effective dose(E)were calculated according to the measurad vales of D.The appropriate precaution times for general adult family members,spouses,coworkers,and children or pregnant women were determined,and the relationships between and precaution time for different close-contact groups were derived by curve-fitting the corresponding data.Results:The mean D vahes of 80 patients at distanes of 30 and 100cm were(15.24±11.25)μSv/h and(1.96±2.63)μSv/h,respectively(P<0.05).The mean values and range of precaution time for general adult familymembers,spouses,coworkers,and children or pregnant women were(4.17±16.55),(102.93±49.22),(51.00±61.29),and(34.27±56.90)d(0-90.61),(0-234.01),(0-247.81),and(0-224.69)d,respectively.Furthemore,a logarithmic relationship betwen D and precaution time(Y)was observed for the different groujps.The equations of these relationships were detemined to be Y=-131.569+83.256 lnD_(0) for general adult family mambers,Y=—108.532+83.318 lnD_(0) for spouses,Y=25.470+83.318 lnD,for coworkers,and Y=2.585+83.229 lnD_(0) for children or pregnant women.Conchusions:Some cancer patients treated by ^(125)I-seed brachytherapy emitover-dose levels of γ-rays,necessitatingradiation protection for their close contacts.However,appropriate patient-specific radiation protection fordifferent close contacts can be determined based on the precaution time calculated using the D_(0) value.
Radioprotection was previously considered as a function of hematopoietic stem cells(HSCs).However,recent studies have reported its activity in hematopoietic progenitor cells(HPCs).To address this issue,we compared the radioprotection activity in 2 subsets of HSCs(nHSC1 and 2 populations)and 4 subsets of HPCs(nHPC1–4 populations)of the mouse bone marrow,in relation to their in vitro and in vivo colony-forming activity.Significant radioprotection activity was detected in the nHSC2 population enriched in lymphoid-biased HSCs.Moderate radioprotection activity was detected in nHPC1 and 2 populations enriched in myeloid-biased HPCs.Low radioprotection activity was detected in the nHSC1 enriched in myeloid-biased HSCs.No radioprotection activity was detected in the nHPC3 and 4 populations that included MPP4(LMPP).Single-cell colony assay combined with flow cytometry analysis showed that the nHSC1,nHSC2,nHPC1,and nHPC2 populations had the neutrophils/macrophages/erythroblasts/megakaryocytes(nmEMk)differentiation potential whereas the nHPC3 and 4 populations had only the nm differentiation potential.Varying day 12 spleen colony-forming units(day 12 CFU-S)were detected in the nHSC1,nHSC2,and nHPC1–3 populations,but very few in the nHPC4 population.These data suggested that nmEMk differentiation potential and day 12 CFU-S activity are partially associated with radioprotection activity.Reconstitution analysis showed that sufficient myeloid reconstitution around 12 to 14 days after transplantation was critical for radioprotection.This study implied that radioprotection is specific to neither HSC nor HPC populations,and that lymphoid-biased HSCs and myeloid-biased HPCs as populations play a major role in radioprotection.
Natural extracts and compounds from marine resources have gained intensive scientific and industry attention for radio-protective activities in the past ten years.However,the marine-derived radioprotectants have been studied against UV-rays,gamma(y)-rays and X-rays for more than 30 years.This review aims to identify key marine-derived extracts/compounds and their modes of action studied for radioprotective activities from 1986 to 2019.A comprehensive survey was conducted to establish the trend in terms of the publications each year and the countries of origin.A total of 40 extracts and 34 natural compounds showing radioprotective activities against UV-rays,gamma(y)-rays and X-rays were identified from a range of marine plants and animals.These extracts and compounds are broadly categorized into polysaccharides,phlorotannins,carotenoids and mycosporine-like amino acids(MAAs).Macroalgae and microalgae were found to be the dominant sources of polysaccharides,phlorotannins and carotenoids.MAAs were mainly identified in algae,sponges,sea cucumber and corals that showed significant UV-absorbing activities.A number of radioprotective mechanisms were shown by these compounds,predominantly free radicals scavenging,inhibition of apoptosis,UV-ray absorption and DNA damage-repair signaling pathways.While these bio-discoveries warrant further investigation and development of radioprotective therapeutics,however,the lack of clinical studies is a major obstacle to be tackled in the future.
