Oral Ingestion of AP Collagen Peptide Leads to Systemic Absorption of Gly-Pro-Hyp, Alleviating H2O2-Induced Dermal Fibroblast Aging.

Collagen-derived dipeptides and tripeptides have various physiological activities. In this study, we compared the plasma kinetics of free Hyp, peptide-derived Hyp, Pro-Hyp, cyclo(Pro-Hyp), Hyp-Gly, Gly-Pro-Hyp, and Gly-Pro-Ala after ingestion of four different collagen samples: AP collagen peptide (APCP), general collagen peptide, collagen, and APCP and γ-aminobutyric acid (GABA) combination. Each peptide was measured by high-performance liquid chromatography and triple quadrupole mass spectrometer. We found that, among all the peptides that were analyzed, only Gly-Pro-Hyp was significantly increased after ingestion of APCP compared with that of general collagen peptides and collagen. In addition, ingestion of the APCP and GABA combination improved the absorption efficiency of Gly-Pro-Ala. Finally, we reveal that Gly-Pro-Hyp was effective for preventing H2O2-induced reduction in extracellular matrix (ECM)-related genes, COL1A, elastin, and fibronectin, in dermal fibroblasts. Taken together, APCP significantly enhances the absorption of Gly-Pro-Hyp, which might act as an ECM-associated signaling factor in dermal fibroblasts, and the APCP and GABA combination promotes Gly-Pro-Ala absorption. Clinical Trial Registration number: UMIN000047972.

Iatrogenic right coronary artery occlusion during minimally invasive cardiac surgery-tricuspid annuloplasty-a case report.

Although rare, right coronary artery (RCA) injury is a serious complication of tricuspid annuloplasty (TAP) and warrants close attention. We report a case of ST elevation myocardial infarction secondary to iatrogenic RCA occlusion during minimally invasive cardiac surgery (MICS). Electrocardiography (ECG) revealed ST segment elevation in lead II. Transesophageal echocardiography (TEE) revealed inferior wall hypokinesis after cardiopulmonary bypass, and coronary angiography revealed peripheral RCA occlusion. Intraoperatively, we detected an atrioventricular groove deformity during the second surgical procedure. Wall motion and ECG abnormalities showed normalization after TAP was reestablished. Vigilant monitoring using TEE and ECG is important to detect intraoperative myocardial ischemia during MICS-TAP.

4ß-Hydroxywithanolide E and withanolide E from Physalis peruviana L. inhibit adipocyte differentiation of 3T3-L1 cells through modulation of mitotic clonal expansion.

Obesity is a risk factor for many diseases, including type 2 diabetes and cardiovascular disease, and is related to the rising morbidity and mortality. Discovery of agents targeting adipogenesis, especially from natural sources, is important for the treatment of obesity. Here, we aimed to identify anti-adipogenic substances in methanol extracts of Physalis peruviana and to investigate their effect, along with underlying mechanisms. Activity-guided fractionation of the extract revealed 4ß-hydroxywithanolide E (HWE) and withanolide E (WE) as the adipogenesis inhibitors. Both compounds suppressed mRNA expression of central adipogenic transcription factors, peroxisome proliferator-activated receptor γ, and CCAAT/enhancer-binding protein α in the early stage of adipocyte differentiation. The inhibitory action of these two withanolides on adipogenesis was largely limited to this stage. The proliferation of preadipocytes was markedly suppressed by treatment with HWE and WE for 24 and 48 h in the differentiation medium, and cell-cycle arrest in the G0/G1 phase was observed. Therefore, our results suggested that withanolides from P. peruviana to be novel anti-adipogenic compounds that modulate mitotic clonal expansion.

Antioxidative attributes of rice bran extracts in ameliorative effects of atherosclerosis-associated risk factors.

Oxidative stress, chronic inflammation, dyslipidemia, hyperglycemia, and shear stress (physical effect) are risk factors associated with the pathogenesis of atherosclerosis. Rice bran, a by-product of rice milling process, is known to house polyphenols and vitamins which exhibit potent antioxidant and anti-inflammatory properties. Through recent emerging knowledge of rice bran in health and wellness, the present study was aimed to assess the ameliorative effects of rice bran extracts (RBE) derived from Japanese colored rice varieties in modulating risk factors of atherosclerosis via in vitro and in vivo study models. Pre-treatment of lipopolysaccharide (LPS)-stimulated murine J774A.1 macrophage-like cells with RBE alleviated nitric oxide (NO) overproduction and downregulated gene expressions of pro-inflammatory modulators: tumor necrosis factor-α (TNF-α), interleukin (IL)-α (IL-1α), IL-1ß, IL-6, and inducible nitric oxide synthase (iNOS). In addition, RBE also significantly attenuated LPS-stimulated protein expressions of iNOS, TNF-α, IL-1α, and IL-6 in J774A.1 macrophage-like cells as compared to non-treated LPS control group. In in vivo, 12 weeks of RBE dietary supplementations significantly reduced (p < 0.05) total cholesterol, triglycerides, and pro-atherogenic oxidized LDL/ß2-glycoprotein I (oxLDL/ß2GPI) complexes at plasma levels, in high fat diet (HFD) induced low density lipoprotein receptor knockout (Ldlr -/-) mice. En face pathological assessments of murine aortas also revealed significant reductions by 38% (p < 0.05) in plaque sizes of RBE-supplemented HFD mice groups as compared to non RBE-supplemented HFD control mice group. Moreover, gene expressions of aortic (iNOS, TNF-α, IL-1ß) and hepatic (TNF-α, IL-1α, IL-1ß) pro-inflammatory modulators were also downregulated in RBE-supplemented mice groups. Present study has revealed the potent health attributes and application of RBE as a dietary supplement to attenuate risks of inadvertent oxidative damage and chronic inflammation underlying the pathogenesis of atherosclerosis. Intrinsically, present preliminary findings may provide global health prospects for future dietary implementation of RBE in management of atherosclerosis.

Tithonia diversifolia-derived orizabin suppresses cell adhesion, differentiation, and oxidized LDL accumulation by Akt signaling suppression via PTEN promotion in THP-1 cells.

As a Japanese folk medicine, Tithonia diversifolia is used for cardiovascular disease prevention and health maintenance. We isolated T. diversifolia-derived orizabin based on the nitric oxide production inhibitory effect. This study aimed to consider orizabin as a novel functional compound with anti-atherosclerotic activity. Orizabin significantly inhibited the adhesion of THP-1 cells to human umbilical vein endothelial cells (HUVECs) and suppressed the mRNA expression of adhesion molecules in HUVECs. In Phorbol 12-myristate 13-acetate stimulated THP-1 cells, orizabin suppressed macrophage differentiation, CD36 expression (1% at 10 µM), and NFκB transcriptional activity. Furthermore, orizabin suppressed oxidized low-density lipoprotein (oxLDL) uptake in macrophages and the Akt phosphorylation. On the contrary, we revealed that phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase (PTEN) mRNA and protein expression were promoted significantly by orizabin (mRNA, 270-fold at 10 µM). Our study presented the possibility that T. diversifolia-derived orizabin is novel anti-atherosclerotic compound via the suppression of Akt phosphorylation, and T. diversifolia may be effective as a new crop for vascular health maintenance. PRACTICAL APPLICATIONS: In this study, the differentiation of monocytes was suppressed without any toxicity, it was obvious in the image, and the oxLDL uptake in monocytes was clearly suppressed by orizabin. Our findings presented that T. diversifolia-derived compound orizabin specifically contributes to the promotion of PTEN expression and suppression of Akt signal in cells, and acts to suppress inflammation by suppression of NFκB transcriptional activity. As a component derived from food, it has a strong function and can be used to maintain the health for blood vessels. It is also a finding that deserves to expand production currently being carried out on a small scale. Furthermore, the promoting effect of PTEN known as a cancer suppressor in orizabin may result in further use for pharmaceuticals research. Orizabin can be safely used as a food-derived compound for maintaining human health.

Fluorinated Kavalactone Inhibited RANKL-Induced Osteoclast Differentiation of RAW264 Cells.

Bone loss and bone-related disease are associated with the deregulation of osteoclast function, and therefore agents that affect osteoclastogenesis have attracted attention. The purpose of the present study was to discover modified kavalactone analogs as potential anti-osteoclastogenic agents. We assessed the effect of 26 analogs on osteoclast differentiation in vitro. The most potent compound, (E)-6-(2-fluorostyryl)-4-methoxy-2H-pyran-2-one (22), suppressed receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenic differentiation of RAW264 cells with IC50 values of 4.3 µM. A partial structure-activity relationship study revealed the importance of fluorine and its position within the 5,6-dehydrokawain skeleton. The results of a pit formation assay suggested that compound 22 prevents osteoclastic bone resorption by inhibiting osteoclastogenesis. Moreover, compound 22 downregulated mRNA expression levels of RANKL-induced nuclear factor of activated T cells c1 (NFATc1) and osteoclastogenesis-related genes. These results suggest that (E)-6-(2-fluorostyryl)-4-methoxy-2H-pyran-2-one scaffold could lead to the identification of new anti-resorptive agents.

Novel Method to Quantify ß-Glucan in Processed Foods: Sodium Hypochlorite Extracting and Enzymatic Digesting (SEED) Assay.

Some ß-glucans have attracted attention due to their functionality as an immunostimulant and have been used in processed foods. However, accurately measuring the ß-glucan content of processed foods using existing methods is difficult. We demonstrate a new method, the Sodium hypochlorite Extracting and Enzymatic Digesting (SEED) assay, in which ß-glucan is extracted using sodium hypochlorite, dimethyl sulfoxide, and 5 mol/L sodium hydroxide and then digested into ß-glucan fragments using Westase which is an enzyme having ß-1,6- and ß-1,3 glucanase activity. The ß-glucan fragments are further digested into glucose using exo-1,3-ß-d-glucanase and ß-glucosidase. We measured ß-glucan comprising ß-1,3-, -1,6-, and -1,(3),4- bonds in various polysaccharide reagents and processed foods using our novel method. The SEED assay was able to quantify ß-glucan with good reproducibility, and the recovery rate was >90% for food containing ß-glucan. Therefore, the SEED assay is capable of accurately measuring the ß-glucan content of processed foods.

Synthesis of novel 5,6-dehydrokawain analogs as osteogenic inducers and their action mechanisms.

An imbalance between bone resorption by osteoclasts and bone formation by osteoblasts can cause bone loss and bone-related disease. In a previous search for natural products that increase osteogenic activity, we found that 5,6-dehydrokawain (1) from Alpinia zerumbet promotes osteoblastogenesis. In this study, we synthesized and evaluated series of 5,6-dehydrokawain analogs. Our structure-activity relationships revealed that alkylation of para or meta position of aromatic ring of 1 promote osteogenic activity. Among the potential analogs we synthesized, (E)-6-(4-Ethylstyryl)-4-methoxy-2H-pyran-2-one (14) and (E)-6-(4-Butylstyryl)-4-methoxy-2H-pyran-2-one (21) both significantly up-regulated Runx2 and Osterix mRNA expression at 10µM. These osteogenic activities could be mediated by bone morphogenetic protein (BMP) and activation of p38 MAPK signaling pathways. Compounds 14 and 21 also inhibited RANKL-induced osteoclast differentiation of RAW264 cells. These results indicated that novel 5,6-dehydrokawain analogs not only increase osteogenic activity but also inhibit osteoclast differentiation, and could be potential lead compounds for the development of anti-osteoporosis agents.

Intraoperative cardiac assessment with transesophageal echocardiography for decision-making in cardiac anesthesia.

Transesophageal echocardiography is an invaluable hemodynamic monitoring modality. Extended and anatomically based evaluation of cardiac function with transesophageal echocardiography is essential to prompt and accurate decision-making in anesthetic management during cardiac surgery. Fractional shortening and fractional area changes are indices widely used to assess the global systolic performance of the left ventricle. Monitoring regional function using semi-quantitative scoring has been demonstrated to be a more sensitive indicator of myocardial ischemia. Assessment of left ventricular diastolic function should be performed in a systematic way, measuring transmitral flow, pulmonary venous flow, transmitral color M-mode flow propagation velocity, and mitral annulus tissue Doppler imaging. The unique anatomical features of the right ventricle make echocardiographic evaluation complicated and therefore less frequently employed. Right ventricular fractional area change, tricuspid annular plane systolic excursion, maximal systolic tricuspid annular velocity with tissue Doppler imaging, and myocardial performance index are indices successfully incorporated into intraoperative right ventricular assessment. Left ventricular outflow tract obstruction with systolic anterior motion of the mitral valve may develop after cardiac procedures. Transesophageal echocardiography plays a central role in prevention as well as diagnosis of systolic anterior motion. Transesophageal echocardiography is extremely useful not only for detecting and locating intracardiac air, but also for guiding and evaluating the procedures to remove air. Air is likely to persist in the right and left superior pulmonary vein, left ventricular apex, left atrium, right coronary sinus of Valsalva, and ascending aorta. Accurate evaluation of cardiac function depends on performing TEE examination properly and obtaining optimal images.

High mortality associated with intracardiac and intrapulmonary thromboses after cardiopulmonary bypass.

PURPOSE: Intrapulmonary or intracardiac thrombosis is a rare but catastrophic event following complex cardiothoracic surgery. Although there have been multiple cases reported in the literature, the causes of these events are largely unknown. In this retrospective review, we attempt to identify risk factors and propose possible mechanisms of thromboses after cardiopulmonary bypass (CPB). METHODS: A literature search was conducted using the MEDLINE and EMBASE with these keywords: (intra)pulmonary thrombosis, pulmonary embolism, pulmonary infarction, lung embolism, (intra)cardiac thrombosis, cardiac thrombi, in combination with CPB, extracorporeal membrane oxygenation, deep hypothermic circulatory arrest, or cardiac surgery. Putative risk factors were compiled from reported cases. RESULTS: We identified 34 cases of massive intrapulmonary and/or intracardiac thromboses. All but 2 cases (94.1%) were fatal. Clinical presentations were systemic hypotension and/or pulmonary hypertension, right ventricular failure, and cardiogenic shock in 32 (94.1%) cases. The timing was immediate (<10 min) following hemostatic intervention in 16 cases (47.1%), within 45 min in 8 cases (23.5%), and not reported in the rest. Putative risk factors included antifibrinolytic use (88.2%), congestive heart failure (55.9%), prolonged CPB use (>2 h) (41.1%), and low activated clotting time (<400 s) after initial heparinization (20.6%). The administration of tissue plasminogen activator in 5 cases was ineffective. CONCLUSIONS: Massive thrombosis following cardiac surgery is a highly lethal event with limited treatment options. Particular attention should be paid to the status of thrombin regulatory proteins before protamine and other hemostatic interventions in patients undergoing complex cardiac surgery with antifibrinolytic agents.

Lessons from the aprotinin saga: current perspective on antifibrinolytic therapy in cardiac surgery.

Antifibrinolytic agents have been prophylactically administered to patients undergoing cardiopulmonary bypass (CPB) to reduce postoperative bleeding due to plasmin-mediated coagulation disturbances. After the recent market withdrawal of aprotinin, a potent bovine-derived plasmin inhibitor, two lysine analogs, epsilon-aminocaproic acid and tranexamic acid are currently available for clinical use. Although the use of aprotinin recently raised major concerns about postoperative thrombosis and organ dysfunctions, there is a paucity of information on the potential complications related to lysine analogs. Using the available preclinical and clinical data, we present current perspectives on the hemostatic mechanism and potential harms of antifbirnolytic therapy related to cardiac surgery. Fibrin formation is the critical step for hemostasis at the site of vascular injury, and localized fibrinolytic activity counterbalances excess fibrin formation which might result in vascular occlusion. Inhibition of the endogenous fibrinolytic system may be associated with thrombotic complications in susceptible organs. It is thus important to understand CPB-related changes in endogenous fibrinolytic proteins (e.g., tissue plasminogen activator (tPA), plasminogen) and antifibrinolytic proteins (e.g., alpha(2)-antiplasmin).

Anesthetic management of apicoaortic bypass in patients with severe aortic stenosis.

Apicoaortic bypass (AAB), or apicoaortic conduit insertion, is a conventional surgical method that has been regaining attention due to the aging population and the increasing number of repeat surgeries. The indication for the procedure has been extended as an alternative for aortic stenosis when the usual sternotomy or aortic clamping is considered to be difficult, e.g., in patients with severe calcification of the ascending aorta (porcelain aorta), or in patients with a patent coronary artery bypass graft located adjacent to the posterior surface of the sternum. Herein, we report our recent anesthetic management of three patients undergoing AAB. Once the apicoaortic conduit is inserted, blood from the left ventricle is ejected via two routes, the narrowed native aortic valve and the apicoaortic conduit. Thus, it is necessary to elucidate any change in blood flow after the withdrawal of the extracorporeal circulation, by using intraoperative transesophageal echocardiography. Furthermore, if a rigid apical connector is not used, anastomosis of the cardiac apex and conduit is conducted under ventricular fibrillation without the infusion of cardioplegic solution; thus, patients are deemed likely to suffer increased myocardial damage. As a rigid apical connector was not used in the three present patients, the administraction of adequate catecholamines was needed for the withdrawal of the extracorporeal circulation. In addition, because those undergoing AAB often have extremely poor cardiac reserve preoperatively owing to the administration of adequate catecholamines was needed for the withdrawal of the extracorporeal circulation. In the three present patients, anesthetic management was successful, and there were no intraoperative or immediate postoperative complications.

Effects of charcoal kiln saunas (Jjimjilbang) on psychological states.

This uncontrolled intervention study explored the effects of sauna bathing utilizing residual heat from charcoal kilns (charcoal kiln saunas) on psychological states. Forty-five volunteers (24 males and 21 females; mean age 51.9 years (S.D. 15.7) visiting a bamboo charcoal kiln in Japan participated in the study. They completed a shortened version of the Profile of Mood States (POMS) and State-Trait Anxiety Inventory (STAI) before and after charcoal kiln sauna bathing in order to determine mood and anxiety states. Six factors relating to mood were measured using the POMS: Tension-Anxiety, Depression-Dejection, Anger-Hostility, Vigor, Fatigue, and Confusion. The two anxiety concepts of state anxiety and trait anxiety were also measured. Changes in psychological states before and after sauna bathing were then determined. All mood scales and both manifest anxiety measures were improved after sauna bathing. Charcoal kiln sauna bathing appears to improve mood and decrease anxiety. It is a limitation of this study that this was a descriptive prospective and an uncontrolled intervention study. Further investigation of the improvement of trait anxiety is required.

Newly developed T-wave inversion with cardiac wall-motion abnormality predominantly occurs in middle-aged or elderly women after noncardiac surgery.

PURPOSE: The study was done to determine the characteristics and prevalence of myocardial ischemia with inverted T waves after noncardiac surgery. METHODS: A list of patients who developed electrocardiogram (ECG) T-wave inversion associated with wall-motion abnormalities observed by transthoracic echocardiography (TTE) following noncardiac surgery was generated from the intensive care unit (ICU) medical records database between January 1, 1995, and December 31, 2000. The hospital records of these patients were analyzed retrospectively. RESULTS: Among 4219 patients (2187 men and 2032 women) who were admitted to the ICU after noncardiac surgery, 13 developed myocardial ischemia with inverted T waves postoperatively. All of the patients were middle-aged or elderly women with no history of coronary artery disease; nine of them had undergone intraabdominal surgery. Characteristic ECG findings included inverted T waves in the left precordial leads, which subsequently became prominent with QT prolongation. In all of these patients, wall-motion abnormalities were observed on the anterior wall, but these resolved within 60 days of the episode. Myocardial ischemia was asymptomatic, with neither hemodynamic changes nor adverse cardiac events. CONCLUSION: Newly developed giant negative T waves with QT prolongation in the ECG may indicate myocardial stunning, but do not in themselves imply a poor prognosis. The marked preponderance of middle-aged and elderly women with this type of myocardial ischemia remains to be explained.