Development and repair of NSAIDs-induced small intestinal lesions: relation to COX isozymes and EP receptor subtypes

Intestinal ulcerogenic properties of NSAIDs require the inhibition of both COX-1 and COX-2, and inhibition of COX-1 up-regulates COX-2 expression and PGs produced by COX-2 counteract the deleterious influences of the COX-1 inhibition. These lesions are prevented by PGE2 mediated by EP3/EP4 receptors and functionally associated with stimulation of mucus secretion, inhibition of intestinal contraction or enterobacterial invasion, and down-regulation of cytokine expression. COX/PGE2 also plays an important role in the healing of these lesions, but the COX isozyme responsible for PG production differs depending on the stage of healing; COX-2 in the early stage and COX-1 in the late stage, and the healing-promoting action of PGE2 is mediated by the activation of EP4 receptors, through enhancing angiogenesis via an increase in VEGF expression.     

Acceleration of TDP43 and FUS/TLS protein expressions in the preconditioned hippocampus following repeated transient ischemia

The 43‐kDa transactivation response DNA binding protein (TDP43), fused in sarcoma/translocated in liposarcoma (FUS/TLS), heat shock protein 70 (HSP70), and β‐amyloid (Aβ) are induced and involved in cerebral ischemia, amyotrophic lateral sclerosis (ALS), and Alzheimer's disease (AD), but their relationships in ischemic tolerance have never been examined, although they could be involved in endogenous neuroprotection under ischemic preconditioning. In the present study, Mongolian gerbils were subjected to one or three incidents of basically nonlethal 2‐min transient common carotid arteries occlusion (tCCAO). Hippocampal CA1 neurons were lost only in the 2‐min three times group at 3 and 7 days, which then gradually recovered from 1 to 6 months. Inductions of TDP43 and FUS/TLS were accelerated from 3 months to 7 days or from 7 days to 1 day, respectively, after 2‐min three times ischemia compared with once. The cytoplasmic stainings of TDP43 and FUS/TLS showed a further acceleration of the peaks from 1 months to 3 days or from 1 months to 7 days, respectively, after 2‐min three times ischemia compared with once. In contrast, HSP70 was induced only at 7 days after 2‐min tCCAO for three times, with no expression for Aβ. These data show that ischemic preconditioning offers a way to induce endogenous neuroprotection and neurogenesis in gerbils, with TDP43, FUS/TLS, and HSP70 involved in this function. © 2013 Wiley Periodicals, Inc.     

Effects of hesperidin on the progression of hypercholesterolemia and fatty liver induced by high-cholesterol diet in rats

The protective effects of hesperidin against hypercholesterolemia and fatty liver were examined in male Wistar rats fed a high-cholesterol diet for 12 weeks. Compared with a standard diet, a high-cholesterol diet not only increased body weights, liver weights, and serum concentration of cholesterol, but also induced the fatty degeneration (steatosis) of liver. Hesperidin (0.08%) reduced levels of hepatic steatosis, adipose tissue and liver weights (P < 0.05), serum total cholesterol and retinol binding protein (RBP) 4 concentrations (P < 0.05) in rats fed with high-cholesterol diet, while reduction in low-density lipoprotein cholesterol levels and triglyceride concentrations was not significant. It also attenuated the marked changes in mRNA expression of lipid metabolism-related proteins: RBP, heart fatty acid-binding protein (H-FABP), and cutaneous fatty acid-binding protein (C-FABP), in liver and adipose tissue. According to the results of gas chromatography, serum concentrations of total cholesterol and biomarkers of cholesterol synthesis (lathosterol) and absorption (campesterol, β-sitosterol) were lower, and concentrations of cholesterol in feces were higher in the rats given hesperidin (P < 0.05). Hesperidin may improve hypercholesterolemia and fatty liver by inhibiting both the synthesis and absorption of cholesterol and regulating the expression of mRNA for RBP, C-FABP, and H-FABP.     

Impact of detection of bacterial endotoxin in menstrual effluent on the pregnancy rate in in vitro fertilization and embryo transfer

OBJECTIVE: To examine whether bacterial endotoxin is detectable in menstrual effluent and to analyze a possible association between endotoxin levels and a pregnancy rate after IVF-ET. DESIGN: Prospective observational study. SETTING: University hospital. PATIENT(S): Thirty-eight infertile women undergoing endotoxin assay and IVF-ET. INTERVENTION(S): Endotoxin was assayed by the limulus amoebocyte lysate test. MAIN OUTCOME MEASURE(S): Levels of bacterial endotoxin and a pregnancy rate. RESULT(S): In 38 samples of menstrual effluent taken from 38 women, bacterial endotoxin was detected with a range of 7.1 to >1,000 pg/mL in 37 samples and was not detected in 1 sample. After IVF-ET, pregnancy occurred in 9 of the 38 women. The mean (+/- SD) endotoxin level in these 9 pregnant women was 71.3 +/- 52.5 pg/mL and was significantly lower compared with >236.2 +/- 333.6 pg/mL in the 29 nonpregnant women. All pregnancies occurred in 28 women with an endotoxin level of 200 pg/mL, producing the significantly higher pregnancy rate in the former group than in the latter. CONCLUSION(S): Bacterial endotoxin was detectable in menstrual effluent from infertile women. The pregnancy rate after IVF-ET was significantly higher in women with an endotoxin level of 200.0 pg/mL.     

Drug development from natural fermentation products: establishing a manufacturing process which maximizes the potential of microorganisms

Natural fermentation products have long been studied as attractive targets for drug discovery due to their amazing diverse, complex chemical structures and biological activities. As such, a number of revolutionary drugs developed from natural fermentation products have contributed to global human health. To commercialize a drug derived from natural fermentation products, an effective chemical entity must be identified and thoroughly researched, and an effective manufacturing process to prepare a commercial supply must be developed. To construct such a manufacturing process for tacrolimus and micafungin, the following studies were conducted: first, we focused on controlling the production of the tacrolimus-related compound FR900525, a fermentation by-product of tacrolimus which was critical for quality assurance of the drug substance. FR900525 production was reduced by using a mutant strain which produced more pipecolic acid, the biosynthesis material of tacrolimus, than the original strain. Then, to optimize the fermentation process of FR901379, an intermediate of micafungin, a fed-batch culture was adopted to increase FR901379 productivity. Additionally, FULLZONE(TM) impeller was installed into the scaled-up fermenter, reducing the agitation-induced damage to the mycelium. As a result, the mycelial form changed from filamentous to pellet-shaped, and the air uptake rate during fermentation was drastically improved. Finally, we conducted screening for FR901379 acylase-producing microorganisms, as FR901379 acylase is necessary to manufacture micafungin. We were able to easily discover FR901379 acylase-producing microorganisms in soil samples using our novel, convenient screening method, which involves comparing the difference in antibiotic activity between FR901379 and its deacylated product.     

Hepatic resection for primary liver malignancy

The results of hepatic resection for patients with primary liver malignancy seen at our clinic during the past 21 years are reported. Of 92 patients, 57 had cirrhosis in addition to hepatocellular carcinoma, and 49 (53 percent) underwent hepatic resection of various degrees from partial resection to trisegmentectomy. Resectability rates of the liver were 52 percent in 77 patients with hepatocellular carcinoma, including 19 in whom the tumor was less than 5 cm in diameter, and 60 percent in 15 patients with other malignant tumors; operative mortality rates were 15 percent in the former and 0 percent in the latter. Cumulative survival rates of all patients who underwent hepatic resection, excluding death within one month, were 55 percent at one year, 29 at 3 and 5 years. In patients with hepatocellularcarcinoma, survival rates of 15 those who had a curative resection of the tumor were 87 percent at one year and 47 percent at 3 or 5 years, there was a significant difference in survival curves between those with tumors less than 5 cm and more than 5 cm (p<0.05). On the other hand, survival rates of all patients with other malignant tumors were 78 percent at one year and 37 percent at 5 years. These results indicate the importance of performing hepatic resection for patients with small hepatocellular carcinoma associated with cirrhosis and those with other malignant tumors.     

Detection of bone marrow and extramedullary involvement in patients with non-Hodgkin’s lymphoma by whole-body MRI: comparison with bone and <Superscript>67</Superscript>Ga scintigraphies

The aim of this study was to evaluate the diagnostic potential of whole-body MRI (WB-MRI) for the detection of bone marrow and extramedullary involvement in patients with non-Hodgkins lymphoma. WB-MRI, which was performed on 34 patients, consisted of the recording of T1-weighted spin-echo images and a fast STIR sequence covering the entire skeleton. The WB-MRI findings for bone marrow and extramedullary involvement were compared with those from ⁶⁷Ga and bone scintigraphies and bone marrow biopsy results. Two MRI specialists reviewed the WB-MRI results and two expert radiologists in the field of nuclear medicine reviewed the bone and ⁶⁷Ga scintigraphy findings. Bone marrow and extramedullary involvement of non-Hodgkins lymphoma were confirmed by follow-up radiographs and CT and/or a histological biopsy. The detection rate of WB-MRI was high. More bone marrow involvement was detected by biopsy, and more lesions were detected by scintigraphies. In total, 89 lesions were detected by WB-MRI, whereas 15 were found by biopsy, 5 by ⁶⁷Ga scintigraphy, and 14 by bone scintigraphy. WB-MRI could also detect more extramedullary lesions than ⁶⁷Ga scintigraphy; i.e., 72 lesions were detected by WB-MRI, whereas 54 were discovered by ⁶⁷Ga scintigraphy. WB-MRI is useful for evaluating the involvement of bone marrow and extramedullary lesions throughout the skeleton in patients with non-Hodgkins lymphoma.