Bone marrow mononuclear cell therapy limits myocardial infarct size through vascular endothelial growth factor

Abstract. No prior study has examined the effect of intravenous injection of bone marrow mononuclear cells (MNCs) on myocardial infarction size (IS). We tested the hypothesis that transplantation of MNCs decreases IS through the release of vascular endothelial growth factor (VEGF). Immediately after ligation of the left coronary artery of immunodeficient mice, PBS or MNCs were intravenously administered. Myocardial IS was significantly less in MNCs-treated mice than in PBS-treated mice. Trace experiments showed accumulation of exogenously administered MNCs into the vicinity of infarcted myocardium. Injection of MNCs did not affect capillary density after infarction, but did reduced myocardial cell apoptosis. Blockade of VEGF by a neutralizing antibody or by gene transfer of a soluble form of Flt-1 VEGF receptor diminished the IS-limiting effects of MNCs. In conclusion, injection of MNCs can reduce myocardial IS through the release of VEGF. The MNC therapy for acute myocardial infarction might improve prognosis of patients with myocardial infarction.     

Changes in Smoking Habits and Behaviors Following the Introduction and Spread of Heated Tobacco Products in Japan and Its Effect on FEV1 Decline: A Longitudinal Cohort Study

BackgroundHeated tobacco product (HTP) use in Japan has rapidly increased. Despite this rapid spread, little is known about the health effects of HTP use. We conducted a longitudinal cohort study to investigate the change in smoking habits following the spread of HTP use and its effect on forced expiratory volume in 1 second (FEV₁) decline.MethodsParticipants consisted of a resident population (n = 2,612; mean age, 67.7 years) with FEV₁ measurement in 2012–2014 and 2018–2019, and a worksite population (n = 722; mean age 49.3 years) without FEV₁ data. Participants were categorized as combustible cigarette-only smokers, HTP-only users, dual users, past smokers, and never smokers. The association between smoking group and the change in smoking consumption over a mean 5.6 years was examined. Differences in annual FEV₁ change between smoking groups were examined in the resident population.ResultsPrevalence of HTP-only and dual users in 2018–2019 was 0.8% and 0.6% in the resident population, and 5.0% and 1.9% in the worksite population, respectively. The overall number of tobacco products smoked/used increased in dual users compared to baseline, but not in others. Annual FEV₁ decline in dual users tended to be greater than that in cigarette-only smokers (16; 95% confidence interval, −34 to 2 mL/year after full adjustment). Participants switching to HTP-only use 1.7 years before had a similar FEV₁ decline as cigarette-only smokers.ConclusionsHTP use, including dual use, is prevalent even in a rural region of Japan. Dual users appear to smoke/use tobacco products more and have a greater FEV₁ decline. Tobacco policy should consider dual use as high-risk.Key words: heated tobacco products, electronic nicotine delivery devices, prevention, smoking caused disease     

Structural determination of a new mutagenic heterocydic amine, 2-amino-1,7,9-trimethylimidazo[4,5-g]quinoxaline (7,9-DiMeIgQx), present in beef extract

We previously found two new mutagens, compounds I and II, inbacteriological-grade beef extract by monitoring the mutagenicityto a new Salmonella strain, YG1024; compound I was identifiedas 2-amino-4-hydroxymethyl-3,8-dimethyli-midazo[4,5-f]quinoxaline(4-CH₂OH-8-MeIQX) In the present study, we isolated compoundII from the beef extract, which accounted for 2% of the totalmutagenicity of materials adsorbed on blue cotton. Further,we found that a large quantity of compound II was produced byheating a mixture of creatine, threonine and glucose (1:1:0.5)at 200^°C for 5 h, the level being 860-fold of that in thebeef extract. The structure of this compound was determinedto be 2-amino-1,7,9-trimethylimidazo[4,5-g]quinoxaline (7,9-DiMeIgQx)by X-ray crystallography. The amount of 7,9-DiMeIgQx in bacteriological-gradebeef extract was estimated to be 53 ng/g. This compound induced13 800 and 670 revertants of S.typhimurium YG1024 and TA98 respectively,per µg in the presence of S9 mix.     

p53 Gene Mutations in Human Prostate Cancers in Japan: Different Mutation Spectra between Japan and Western Countries

The involvement of p53 mutations in prostate cancers in Japan was investigated. To evaluate any possible clinicopathological significance, p53 mutations in 40 samples from 36 Japanese prostate cancers of different stages (five cases of latent tumors, three of stage A cancers, 10 of stage B, five of stage C and 13 of stage D), including four lymph node metastases of stage D cases, were examined by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis and sequencing. Mutations were detected in five of 40 samples (12.5%); four were in primary cancers and the other in a lymph node metastasis from one of them. All mutation-positive cases were in stage D, and the mutation frequency in stage D cases was 31%. This result indicates that p53 mutations may play a role in the progression of a subgroup of prostate cancers in Japanese, as observed for Americans and Europeans. However, a difference was noted between Japanese and Americans in the p53 mutational spectrum (at CpG site), presumably arising from variation in the underlying etiotogic factors.     

Decreased Levels of 2-Amino-3-methylimidazo[4,5-f]quinoline-DNA Adducts in Rats Treated with β-Carotene, α-Tocopherol and Freeze-dried Aloe

To assess mechanisms of chemoprevention of hepatocarcinogenesis by trans -β-carotene (β-C), DL-α-tocopherol (α-T), and freeze-dried whole leaves of Kidachi aloe (Aloe), formation of 2-amino-3-methylimidazo[4,5- f ]quinoline (IQ)-DNA adducts was measured by ³²P-post-labeling analysis, and CYP1A1 and CYP1A2 protein levels were analyzed by ELISA. Group 1 rats were fed diet containing 0.02%β-C, 1.5%α-T or 30% Aloe over an 8-day period, while group 2 was given basal diet alone. On day 7, all animals were subjected to two-thirds partial hepatectomy (PH). Twelve hours after PH, they received a single dose of the carcinogenic food pyrolysate IQ (100 mg/kg) intragastrically, to initiate hepatocarcinogenesis. Rats were killed 6, 12, 24 and 48 h after IQ administration. The levels of adducts, expressed as relative adduct labeling values in rats treated with β-C, α-T and Aloe, were decreased as compared with the control group at hour 24 (36 h after PH), with a significant difference in the case of the β-C group (46.4% of the control value). Similarly, all showed a tendency for decrease at hour 48. Furthermore, the levels of CYP1A2, known to be responsible for activation of IQ, showed a significant reduction at hour 24. It is concluded that β-C, and possibly also α-T and Aloe, have the potential to reduce IQ-DNA adduct formation, presumably as a result of decreased formation of active metabolites. The results may explain, at least in part, the previously observed inhibitory effects of these compounds on induction of preneoplastic hepatocellular lesions.     

DNA adduct formation, cell proliferation and aberrant crypt focus formation induced by PhIP in male and female rat colon with relevance to carcinogenesis

2-Amino-1-methyl-6-phenylimidazo[4, 5-b]pyridine (PhIP) inducescolon tumors in male, but not female, F344 rats, We investigatedthe mechanisms leading to this difference by measuring the levelof PhlP-DNA adducts, the enhancement of cell proliferation andaberrant crypt focus (ACF) formation in colon mucosa. PhIP wasadministered in the diet at a level of 0.04% to both male andfemale F344 rats for 1–8 weeks. The level of DNA adductsin the colon mucosa was measured using the ³²P-postlabelingmethod. Four major PhlP-DNA adducts were detected in fairlyconstant proportions in all the animals examined. The levelof PhlP-DNA adducts in male and female rats was the same, indicatingno direct correlation between adduct levels and carcinogenesis.Labeling indices (LIs) were determined by measuring BrdU incorporationin rats after feeding with a PhIP diet for 4, 8 and 12 weeks.After 8 weeks administration the LI had increased 1.5-fold inthe colon of the male rats, but no increase was observed inthe female rats. ACF formation was examined after feeding witha PhIP diet for 14 weeks. The number of aberrant crypt fociwas 6.6 ± 1.5 per rat in males and 1.9 ± 0.5 perrat in females. Thus differences in colon tumor developmentin male and female rats takes place at an early stage(s). Ourresults suggest that, in addition to DNA adduct formation, enhancedproliferation contribites to the formation of ACFs, which arepremalignant lesions of the colon.     

Predictive value of blood flow in the gastric tube in anastomotic insufficiency after thoracic esophagectomy

Anastomotic insufficiency is considered to be one of the most serious complications associated with esophageal reconstruction. The purposes of this study were to identify (1) the relationship between anastomotic insufficiency and tissue blood flow (TBF) in the gastric tube in the perioperative period, and (2) the effects of intravenous prostaglandin E1 (PGE1) on TBF in the gastric tube. The study group consisted of 44 patients who were to undergo esophagectomy for esophageal cancer. Intraoperative and postoperative TBF on the serosal side of the gastric tube were measured by laser-Doppler tissue blood flowmetry. The TBF of the Leakage(+) group (n = 5) was poorer than that of the Leakage(?) group (n = 39) during the intraoperative and postoperative periods. There was a significant difference in TBF between the two groups at postoperative day (POD) 3. There was a tendency in the PGE1(+) group (n = 18) to exhibit richer blood flow through the anastomosis than the PGE1(?) group (n = 26), intraoperatively, but the difference was not significant. Two of five Leakage(+) cases were also in the PGE1(+) group. There was no relationship between intraoperative medication with PGE1 and incidence of leakage. The TBF of three-field lymph node dissection and reconstruction of the retrosternal route group (n = 21) was poorer than that of the two-field lymph-node dissection and reconstruction of the posterior mediastinal route group (n = 23). The TBF in the gastric tube after esophagectomy may be a predictor of anastomotic insufficiency. However, PGE1 treatment in the intraoperative period alone is not effective in preventing anastomotic insufficiency.