Cancer-protective effect of a synbiotic combination between Lactobacillus gasseri 505 and a Cudrania tricuspidata leaf extract on colitis-associated colorectal cancer

ABSTRACT

Previously, a synbiotic combination of probiotic Lactobacillus gasseri 505 (LG) and a new prebiotic, Cudrania tricuspidata leaf extract (CT) in fermented milk, designated FCT, showed an in vitro immunomodulatory effect and antioxidant activity. Although synbiotic combination might have cancer-protective effects, these activities have not been fully validated in vivo. Ten-week treatment of LG, CT, or FCT to azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colitis-associated colorectal cancer (CAC) mouse model reduced both the incidence of colonic tumors and damage to the colonic mucosa effectively, suggesting a cancer-protective effect. To understand these, biomarkers associated with inflammation, colon barrier, apoptosis, and cancer cell proliferation were monitored in AOM/DSS group versus LG/CT/FCT groups. A synbiotic combination (FCT) down-regulated pro-inflammatory cytokines (TNF-α, IFN-γ, IL-1β, and IL-6) and inflammation-associated enzymes (iNOS and COX-2), and up-regulated anti-inflammatory cytokines (IL-4 and IL-10). In addition, colon barrier experiment revealed that biomarkers of mucus layer (MUC-2 and TFF3) and tight junction (occludin and ZO-1) were up-regulated. Subsequent apoptosis experiment showed that pro-apoptotic factors (p53, p21, and Bax) were up-regulated and anti-apoptotic factors (Bcl-2 and Bcl-xL) were down-regulated. Furthermore, comparative metagenome analysis of gut microbiota revealed that Staphylococcus decreased but Lactobacillus, Bifidobacterium, and Akkermansia increased, supporting their protective effects, accompanied by increased short-chain fatty acids (SCFAs). Taken together, the FCT administration showed cancer-protective effects by reducing the risk of colitis-associated colon cancer via regulation of inflammation, carcinogenesis, and compositional change of gut microbiota. Consequently, the synbiotic combination (FCT) could be a novel potential health-protective natural agent against CAC.     

Randomized trial of candesartan cilexetil in the treatment of patients with congestive heart failure and a history of intolerance to angiotensin-converting enzyme inhibitors

BACKGROUND: Many patients with congestive heart failure do not receive the benefits of angiotensin-converting enzyme (ACE) inhibitors because of intolerance. We sought to determine the tolerability of an angiotensin II receptor blocker, candesartan cilexetil, among patients considered intolerant of ACE inhibitors. METHODS: Patients with CHF, left ventricular ejection fraction less than 35%, and history of discontinuing an ACE inhibitor because of intolerance underwent double-blind randomization in a 2:1 ratio to receive candesartan (n = 179) or a placebo (n = 91). The initial dosage of candesartan was 4 mg/d; the dosage was increased to 16 mg/d if the drug was tolerated. A history of intolerance of ACE inhibitor was attributed to cough (67% of patients), hypotension (15%), or renal dysfunction (11%). RESULTS: The study drug was continued for 12 weeks by 82.7% of patients who received candesartan versus 86.8% of patients who received the placebo. This 4.1% greater discontinuation rate with active therapy was not significant; the 95% confidence interval ranged from 4.8% more discontinuation with placebo to 13% more with candesartan. Titration to the 16-mg target dose was possible for 69% of patients who received candesartan versus 84% of those who received the placebo. Frequencies of death and morbidity were not significantly different between the candesartan and placebo groups (death 3.4% and 3.3%, worsening heart failure 8.4% and 13.2%, myocardial infarction 2.8% and 5.5%, all-cause hospitalization 12.8% and 18.7%, and death or hospitalization for heart failure 11.7% and 14.3%). CONCLUSIONS: Candesartan was well tolerated by this population. The effect of candesartan on major clinical end points, including death, remains to be determined.     

Effect of hyperinsulinemia on myocardial amino acid uptake in patients with coronary artery disease

Branched-chain amino acids (BCAAs) are oxidative energy substrates for the heart and may exert anabolic effects on myocardial protein. The factors regulating their myocardial uptake in patients with ischemic heart disease are therefore of interest. To examine whether myocardial BCAA utilization is influenced by the circulating insulin concentration, in 10 patients with chronic ischemic heart disease, we measured transmyocardial amino acid balance during fasting and again during a 90-minute euglycemic insulin infusion (plasma insulin, 218+/-25 microU x mL(-1)) with plasma BCAA concentrations held constant by coinfusion. In the fasting state, the myocardial fractional extraction of leucine (8%), isoleucine (9%), and valine (5%) from arterial plasma was slightly greater than that of glucose (3%), while net myocardial BCAA uptake (leucine, 409+/-207 nmol x min(-1); isoleucine, 220+/-144 nmol x min(-1); valine, 407+/-326 nmol x min(-1); and total BCAA uptake, 1.0+/-0.3 micromol x min(-1)) was about 13% that of glucose (8+/-2 micromol x min(-1)). During euglycemic hyperinsulinemia, myocardial glucose uptake increased 3-fold, but there was no change in the arterial-coronary sinus balance or net myocardial uptake of any BCAA under conditions where their plasma concentrations were held constant. Instead, the myocardial uptake of each BCAA correlated positively with its concentration in arterial plasma. These results demonstrate that in patients with cardiovascular disease, myocardial utilization of BCAAs is insensitive to the circulating insulin level and is regulated instead by their availability in arterial plasma. Hyperinsulinemia reduced the magnitude of both net glutamate uptake and alanine release, suggesting a possible salutary effect on myocardial oxidative efficiency.     

NAD(P)H oxidase-dependent platelet superoxide anion release increases platelet recruitment

Platelets, although not phagocytotic, have been suggested to release O. Since O-producing reduced nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) oxidases can be specifically activated by certain agonists and are found in several nonphagocytotic tissues, we investigated whether such an enzyme is the source of platelet-derived O. We further studied which agonists cause platelet O release and whether platelet-derived O influences thrombus formation in vitro. Collagen, but not adenosine 5'-diphosphate (ADP) or thrombin, increased O formation in washed human platelets. This was a reduced nicotinamide adenine dinucleotide (NADH)-dependent process, as shown in platelet lysates. Consistent with a role of a platelet, NAD(P)H oxidase expression of its subunits p47(phox) and p67(phox) and inhibition of platelet O formation by diphenylene-iodoniumchloride (DPI) and by the specific peptide-antagonist gp91ds-tat were observed. Whereas platelet-derived O did not influence initial aggregation, platelet recruitment to a preformed thrombus following collagen stimulation was significantly attenuated by superoxide dismutase (SOD) or DPI. It was also inhibited when ADP released during aggregation was cleaved by the ectonucleotidase apyrase. ADP in supernatants of collagen-activated platelets was decreased in the presence of SOD, resulting in lower ADP concentrations available for recruitment of further platelets. Exogenous O increased ADP- concentrations in supernatants of collagen-stimulated platelets and induced irreversible aggregation when platelets were stimulated with otherwise subthreshold concentrations of ADP. These results strongly suggest that collagen activation induces NAD(P)H oxidase-dependent O release in platelets, which in turn enhances availability of released ADP, resulting in increased platelet recruitment.     

Two cases of pancreatic ductal adenocarcinoma, manifested as solid pseudopapillary tumor and intraductal papillary mucinous neoplasm]

Compared with other types of cancers, pancreatic cancer is one of the most dreadful malignancies and is fifth leading cause of cancer-related death in Korea. It is difficult to expect early diagnosis or improvement in prognosis due to lack of specific early symptoms and effective diagnostic methods. Whereas cystic neoplasm of the pancreas is a rare type of pancreatic tumor, surgical resection provides good prognosis because of its low possibility of local invasion or distant metastasis. In case of pancreatic cystic tumor, radiologic differentiation between benign and malignant lesions is crucial for the selection of appropriate treatment and the prediction of prognosis. And ductal adenocarcinoma of pancreas presenting in cystic form is an uncommon type of cystic tumor, making it extremely rare among all pancreatic malignancies. We report two cases of atypical pancreatic ductal adenocarcinoma presenting as solid pseudopapillary tumor and intraductal papillary mucinous neoplasm, respectively.     

Factors determining early left atrial reverse remodeling after mitral valve surgery

This study aimed to investigate the factors determining early left atrial (LA) reverse remodeling after mitral valve (MV) surgery. The left atrium is frequently dilated in patients with mitral stenosis (MS) or mitral regurgitation (MR). MV surgery usually results in LA volume reduction. However, the factors associated with LA reverse remodeling after MV surgery are not clearly defined. One hundred thirty-eight patients (51 men, 87 women; mean age, 53 years) underwent transthoracic echocardiography before and after MV surgery. Maximal LA volume was measured using the prolate ellipsoid model. The percentage of LA volume change was calculated. The patients were grouped according to age (<50 vs >or=50 years), predominant lesion (pure MR vs some degree of MS), type of surgery (MV repair vs MV replacement), and preoperative rhythm (sinus rhythm vs atrial fibrillation). LA volume decreased from 147+/-93 to 103+/-43 ml (p<0.001) after surgery. LA reverse remodeling was more prominent in patients who were <50 years old (percentage of LA volume change -31.2+/-17.4 vs -18.4+/-19.2, p<0.001), had pure MR (percentage of LA volume change -30.4+/-18.6 vs -17.3+/-18.2, p<0.001), and had a preoperative sinus rhythm (percentage of LA volume change -28.5+/-17.7 vs -20.5+/-20.0, p=0.019). In conclusion, on stepwise multiple regression analysis, preoperative LA volume, predominant lesion, age, and cardiac rhythm were significant predictors of LA reverse remodeling. A larger preoperative LA volume, MR rather than MS, younger age at the time of surgery, and sinus rhythm were important predictors of LA reverse remodeling after MV surgery.     

Is albuminuria an indicator of myocardial dysfunction in diabetic patients without overt heart disease? A study with Doppler strain and strain rate imaging

The aim of this study was to address whether albuminuria could predict myocardial dysfunction in diabetic patients without overt heart disease. We studied 67 patients with normal left ventricular (LV) ejection fraction and no evidence of LV hypertrophy or coronary artery disease (47 patients with type 2 diabetes mellitus and hypertension and 20 patients with hypertension only). Diabetes patients were divided into 3 groups based on albuminuria status: group II = no albuminuria (n = 20, <30 mg/d), group III = microalbuminuria (n = 13, 30-300 mg/d), and group IV = macroalbuminuria (n = 14, >300 mg/d). Twenty patients with hypertension only served as a control group (group I). Conventional 2-dimensional and Doppler echocardiography was done. Peak strain, peak systolic strain rate (SR), and peak diastolic SR of 6 LV segments in the apical views were measured and averaged in each patient. Conventional 2-dimensional parameters such as LV ejection fraction; left atrium volume index; LV mass; deceleration time; and mitral early peak, mitral late peak, myocardial early peak diastolic, and myocardial peak systolic velocities were not different among the 4 groups. However, peak strains were significantly lower in group III (P = .002) and group IV (P < .001) than in group I; and the absolute value of peak systolic SR was lower in group III (P = .033) and group IV (P < .001) than in group I. Furthermore, the value of peak diastolic SR was lower in group IV than in group I (P = .014). In diabetic patients with albuminuria, Doppler strain and SR imaging detected subclinical LV systolic and diastolic dysfunction; and albuminuria was associated with myocardial dysfunction in diabetic patients without overt heart disease.     

Nucleic acid-specific suppressor T cells.

The concept of using cell-bound antigens as tolerogen was applied to nucleic acid. Nucleoside was linked directly to spleen cell suspensions. Intravenous administration of nucleoside coupled to isogeneic spleen cells into mice generated suppressor cells that diminished the formation of antibody-forming cells either to a T-dependent antigen in vivo or to a T-independent antigen in vitro. Suppressor cells were nucleoside specific, but the specificity of immune suppression seems to be somewhat broader than that of tolerance to a single nucleoside. The ability to raise nucleic acid-specific suppressor T cells may have implications for both the pathogenesis and treatment of systemic lupus erythematosus.