Kazuya Kitamori

SERUM LIPID EFFECTS OF A MONOUNSATURATED (PALMITOLEIC) FATTY ACID-RICH DIET BASED ON MACADAMIA NUTS IN HEALTHY, YOUNG JAPANESE WOMEN

1. Recent studies have identified potential beneficial effects of eating nuts, most of which have substantial amounts of monounsaturated fatty acids (MUFA). Macadamia nuts consist of 75% fat by weight, 80% of which is MUFA (palmitoleic acid).

The modulation of hepatic adenosine triphosphate and inflammation by eicosapentaenoic acid during severe fibrotic progression in the SHRSP5/Dmcr rat model.

AIMS Eicosapentaenoic acid (EPA) can ameliorate certain liver lesions involved in non-alcoholic steatohepatitis (NASH). A previous study has found that stroke-prone spontaneously hypertensive 5/Dmcr (SHRSP5/Dmcr) rats fed a high fat-cholesterol (HFC) diet developed fibrotic steatohepatitis with histological similarities to NASH. This study evaluated the potential effects and mechanisms of action of EPA supplementation using this rodent model. MAIN METHODS Male rats were randomly assigned to groups that were fed with either the stroke-prone (SP) diet or HFC diet with or without EPA for 2, 8 and 14 weeks, respectively. The liver histopathology, biochemical features, mRNA and protein levels, and nuclear factor-κB (NF-κB) DNA binding activity were determined. KEY FINDINGS The SP diet-fed rats presented normal livers. Conversely, the HFC diet-fed rats developed microvesicular/macrovesicular steatosis, inflammation, ballooning degeneration and severe fibrosis. At 2 weeks, the administration of EPA inhibited hepatic inflammatory recruitment by blocking the phosphorylation of inhibitor of κB-α (IκBα), which antagonizes the NF-κB activation pathway. The dietary supplementation of EPA for 8 weeks ameliorated hepatic triglyceride accumulation and macrovesicular steatosis by inhibiting the HFC diet-induced decrease in the protein levels of enzymes involved in fatty acid β-oxidation including carnitine palmitoyltransferase 1, very long chain acyl-CoA dehydrogenase and peroxisomal bifunctional protein. Although the administration of EPA elicited no histologically detectable effects on severe fibrosis at 14 weeks, it restored an HFC diet-induced decline in hepatic adenosine triphosphate (ATP) levels and suppressed ballooning degeneration, suggesting that EPA may inhibit HFC diet-induced ATP loss and cell death. SIGNIFICANCE Initial amelioration of the inflammation and steatosis in the rats after EPA supplementation indicates a possibility to treat steatohepatitis. Additionally, this study provides new insights into the roles of EPA in hepatic ATP depletion and subsequent hepatocellular injury during severe fibrosis.

Physical activity and cardiovascular disease risk factors among young and middle-aged men in urban Mwanza, Tanzania

Introduction La survenue de l’hypertension artérielle pulmonaire (HTAP) est un tournant dans l’évolution de la sclérodermie. L’objectif de cette étude est de décrire les aspects épidémiologiques et évolutifs de l’HTAP au cours de la sclérodermie systémique. Méthodes Nous avons réalisé une étude descriptive concernant des patients suivis pour sclérodermie systémique, au service de Dermatologie de l’hôpital Aristide Le Dantec entre Janvier 2000 et Août 2009. Ces patients étaient inclus dans l’étude après exploration cardio-vasculaire (ECG, échocardiographie-Doppler). Nous avons étudié les paramètres épidémiologiques, cliniques, paracliniques et évolutifs des patients. Résultats Nous avons enregistré 12 cas d’hypertension artérielle pulmonaire parmi les 83 patients atteints de sclérodermie systémique soit une prévalence de 14,45%. L’âge moyen des patients était de 43,58 ans±12,5 ans et le sex-ratio (H/F) de 0,33. Sur le plan clinique, la dyspnée était quasi constante (75%) et la douleur thoracique présente dans 25% des cas. Le syndrome de Raynaud était observé chez 8 patients soit 66,67% de nos patients. L’électrocardiogramme montrait des signes de surcharge droite chez 4 malades (33,33%) et la radiographie thoracique en faveur d’une fibrose pulmonaire chez 4 patients. L’échocardiographie-Doppler notait une insuffisance tricuspide importante dans 58, 33% des cas (7 patients), une pression artérielle pulmonaire systolique (PAPs) en moyenne de 66,25±29,3 mmHg, une dilatation des cavités cardiaques droites dans 5 cas et un mouvement paradoxal du septum interventriculaire chez 3 malades (33,33%). Il était également noté 3 cas (25%) d’épanchement péricardique. Nous avons déploré 4 décès (33,33%). Conclusion L’hypertension artérielle pulmonaire est une complication fréquente et grave de la sclérodermie. Son dépistage, grâce à l’échocardiographie-Doppler systématique, constitue une étape fondamentale de la prise en charge.Introduction: Some probable mechanisms have been described to the relationship between magnesium (Mg) level and migraine headache attacks. In the study reported here, we sought to determine the total Mg serum status of patients with migraine within and between the headache attacks and compare it with non-migraineurs. Methods: This study was performed on 50 migraineurs patients diagnosed according to the International Headache Society (IHS) criteria for acute migraine headache. Fifty healthy subjects without any family history or evidences of migraine were randomly selected from hospital personnel as the control group. Serum Mg level was measured by Xylidyl blue method. Results: In the group with migraine headache, no significant difference was found in the serum total Mg levels within and between migraine headache attacks (1.86 ± 0.41 mg/dl versus 1.95 ± 0.35 mg/dl, p = 0.224). But, serum total Mg level was notably lower in the group with these attacks compared to the control group (1.86 ± 0.41 mg/dl versus 2.10 ± 0.23 mg/dl, p < 0.001). Conclusion: Serum Mg level is on average significantly reduced in patients with migraine compared to the healthy group. However, the serum total Mg levels in migraineurs remained constant within and between migraine headache attacks.Le kyste hydatique est une parasitose qui sévit à l’état endémique au Maroc. Cependant sa rupture au cours de la grossesse reste rare. Nous rapportons le cas d’une patiente de 23 ans, admise aux urgences en état de choc avec bouffissure du visage sur aménorrhée de 8 semaines, chez laquelle le diagnostic d’hydatidose à la fois hépatique et pelvienne, avec éventuelle rupture de l’un des kystes hépatiques a été posé par la radiologie. Après mesures de réanimation, le traitement chirurgical a été instauré, avec bonne évolution. Nous essayons à partir de ce cas et à travers une revue de littérature, de préciser les difficultés diagnostiques et thérapeutiques rencontrées dans la prise en charge des kystes hydatiques, surtout compliquées, au cours de la grossesse.

High-fat-cholesterol diet mainly induced necrosis in fibrotic steatohepatitis rat by suppressing caspase activity

AIM Apoptosis and necrosis occur in nonalcoholic steatohepatitis (NASH) and are thought to be related to fibrosis. A stroke-prone spontaneously hypertensive (SHRSP5/Dmcr) rat fed a high-fat-cholesterol (HFC) diet exhibited similar pathological features to human NASH with severe liver fibrosis. We aimed to reveal the molecular pathway and to confirm the relationship between cell death, fibrosis and K18Asp396 levels, a neoepitope generated during cleavage of keratin 18 by caspases, as a candidate for biomarker of hepatic damage in this animal model. MAIN METHODS Male rats were fed with control and HFC diets for 2, 8 and 14 weeks. Liver apoptosis cells, necrosis score, and the molecular mechanism and K18Asp396 levels were investigated. KEY FINDINGS HFC diet increased TUNEL-positive cells only at 2 weeks and necrosis scores strongly in the livers of rats during the entire period. This diet increased hepatic Bax/Bak but decreased Bcl-2/Bcl-xl expression during the entire period; however, it upregulated caspase 8, 9, and 3/7 activities only at 2 weeks, but downregulated them at 14 weeks. Additionally, this diet did not increase hepatic cytochrome c expression. Serum K18Asp396 levels have a positive correlation with necrosis score. SIGNIFICANCE In SHRSP5/Dmcr rats, HFC diet caused hepatocyte necrosis rather than apoptosis by the downregulation of all caspase activity. Serum K18Asp396 levels may be a good biomarker of hepatocyte necrosis.

Serial changes in adipocytokines and cardiac function in a rat model of the metabolic syndrome.

Obesity is associated with high chronic cardiac workload due to the need to supply more blood to peripheral tissue, and frequently leads to left ventricular (LV) dysfunction. The present study examined serial changes in cardiac function in the SHR/NDmcr‐cp (SHR/cp) strain, an experimental model of obesity plus hypertension and metabolic syndrome. Transthoracic echocardiography was used to define cardiac dimensions and function in male spontaneously hypertensive rats (SHR/lean), SHR/cp and Wistar‐Kyoto rats. We also assessed age‐related changes in plasma and LV adipocytokine levels in this model. Although there were no significant differences in LV end‐diastolic diameter and end‐systolic diameter among the three rat strains until 24 weeks of age, these parameters were significantly higher and LV fractional shortening (%FS) was significantly lower in SHR/cp compared with SHR/lean at 32 weeks of age. At the same age, pronounced interstitial fibrosis and infiltration of macrophages and T lymphocytes into the LV was noted in SHR/cp relative to the other strains. In the myocardium, adiponectin levels were significantly lower and resistin levels and the expression of proinflammatory cytokines (tumour necrosis factor‐α and interleukin‐6) were significantly higher in SHR/cp than SHR/lean at 32 weeks of age. Using echocardiography, we demonstrated reduced systolic function in 32‐week‐old SHR/cp. Changes in myocardial cytokine concentrations could be involved in worsening of cardiac function in our animal model of metabolic syndrome.

Efficacy of Dietary Lipid Control in Healing High-Fat and High-Cholesterol Diet-Induced Fibrotic Steatohepatitis in Rats.

Nonalcoholic steatohepatitis is related to lifestyle, particularly to dietary habits. We developed diet-induced fibrotic steatohepatitis model stroke-prone spontaneously hypertensive 5/Dmcr (SHRSP5/Dmcr) rats showing steatosis, hepatic inflammation, and severe fibrosis induced by high-fat and -cholesterol (HFC) diet feeding. We aimed to clarify the efficacy of dietary intervention on the disease before and after the appearance of fibrosis. Male SHRSP5/Dmcr rats were divided into 9 groups; of these, 6 groups were fed control or HFC diet for several weeks and the remaining 3 groups represented the dietary intervention groups, which were fed the control diet after HFC diet feeding for 2 (before the appearance of fibrosis) or 8 (after the appearance of fibrosis) weeks. Dietary intervention before the appearance of fibrosis significantly improved the steatosis and reset the increased serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and serum total cholesterol (TC) levels. However, dietary intervention after the appearance of fibrosis was unable to reset the levels of hepatic TC, serum ALT, and fibrogenesis-related markers and had only a minor influence on hepatic fibrosis, although it reset the increased expression of transforming growth factor (TGF)-β1 and α-smooth muscle actin (SMA). It was noted that dietary intervention improved the increased AST levels; however, aggregated CD68-positive cells were still observed around the fibrosis area, which may be related to the findings of inflammatory cytokine mRNAs. Taken together, dietary intervention for fibrotic steatohepatitis improved steatosis, although it could not completely improve fibrosis.

EFFECTS OF DIETARY FIBRE ON SHR/NDmcr-cp (fak/fak) RAT, A MODEL OF METABOLIC SYNDROME

1 SHR/NDmcr‐cp (fak/fak) (CP) rats have a genetic background from spontaneously hypertensive rats and carry a non‐sense mutation of the leptin receptor derived from obese Koletsky rats. CP rats show several metabolic disorders similar to patients with metabolic syndrome. The aim of the present study was to examine whether the intake of a fibre‐supplemented diet prevented the abnormalities in this metabolic syndrome rat model. 2 Male CP rats aged 6 weeks were divided into three groups and fed ad libitum a normal diet (control), a 10% soluble–insoluble fibre mixture diet (MF) and a 10% soluble fibre diet, indigestible dextrin (SF). At 23 weeks of age, abdominal obesity was attenuated in the MF group. Bodyweight gain was significantly reduced in the MF group from 16 weeks of age compared with the control group. 3 Our study suggests that a soluble–insoluble fibre mixture diet may be more effective in the primary prevention of metabolic syndrome than an insoluble diet only.

Combination of Hypertension Along with a High Fat and Cholesterol Diet Induces Severe Hepatic Inflammation in Rats via a Signaling Network Comprising NF-κB, MAPK, and Nrf2 Pathways

Populations with essential hypertension have a high risk of nonalcoholic steatohepatitis (NASH). In this study, we investigated the mechanism that underlies the progression of hypertension-associated NASH by comparing differences in the development of high fat and cholesterol (HFC) diet-induced NASH among three strains of rats, i.e., two hypertensive strains comprising spontaneously hypertensive rats and the stroke-prone spontaneously hypertensive 5/Dmcr, and the original Wistar Kyoto rats as the normotensive control. We investigated histopathological changes and molecular signals related to inflammation in the liver after feeding with the HFC diet for 8 weeks. The diet induced severe lobular inflammation and fibrosis in the livers of the hypertensive rats, whereas it only caused mild steatohepatitis in the normotensive rats. An increased activation of proinflammatory signaling (transforming growth factor-β1/mitogen-activated protein kinases pathway) was observed in the hypertensive strains fed with the HFC diet. In addition, the HFC diet suppressed the nuclear factor erythroid 2-related factor 2 pathway in the hypertensive rats and led to lower increases in the hepatic expression of heme oxygenase-1, which has anti-oxidative and anti-inflammatory activities. In conclusion, these signaling pathways might play crucial roles in the development of hypertension-associated NASH.

A High-Fat and High-Cholesterol Diet Induces Cardiac Fibrosis, Vascular Endothelial, and Left Ventricular Diastolic Dysfunction in SHRSP5/Dmcr Rats

Aim: Non-alcoholic steatohepatitis (NASH) increases cardiovascular risk regardless of risk factors in metabolic syndrome. However, the intermediary factors between NASH and vascular disease are still unknown because a suitable animal model has never been established. The stroke-prone (SP) spontaneously hypertensive rat, SHRSP5/Dmcr, simultaneously develops hypertension, acute arterial lipid deposits in mesenteric arteries, and NASH when feed with a high-fat and high-cholesterol (HFC) diet. We investigated whether SHRSP5/Dmcr affected with NASH aggravates the cardiac or vascular dysfunction. Method: Wister Kyoto and SHRSP5/Dmcr rats were divided into 4 groups of 5 rats each, and fed with a SP or HFC diet. After 8 weeks of HFC or SP diet feeding, glucose and insulin resistance, echocardiography, blood biochemistry, histopathological staining, and endothelial function in aorta were evaluated. Results: We demonstrate that SHRSP5/Dmcr rats fed with a HFC diet presented with cardiac and vascular dysfunction caused by cardiac fibrosis, endothelial dysfunction, and left ventricular diastolic dysfunction, in association with NASH and hypertension. These cardiac and vascular dysfunctions were aggravated and not associated with the presence of hypertension, glucose metabolism disorder, and/or obesity. Conclusions: SHRSP5/Dmcr rats may be a suitable animal model for elucidating the organ interaction between NASH and cardiac or vascular dysfunction.

The Progression of Non-alcoholic Fatty Liver Disease and Lifestyle Intervention in Older Adults

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. It encompasses a spectrum of liver histology in individuals who drink little or no alcohol, ranging from simple fatty liver (steatosis), through fat accompanied by signs of hepatocyte injury, mixed inflammatory cell infiltrate, and variable hepatic fibrosis (non-alcoholic steatohepatitis, NASH), to cirrhosis and hepatocellular carcinoma. Approximately 19.0% of the general United States population has NAFLD, and around 11.8% of NAFLD patients develop NASH. The prevalence, severity, and progression of NAFLD/NASH are significantly associated with the presence of metabolic syndrome components, especially obesity and diabetes, and are also governed by the interactive effects of age, sex, genetic susceptibility, and lifestyle (diet and exercise). In particular, advanced age is associated with disease severity and fibrosis progression. A combination of dietary modification and physical activity is the cornerstone of NAFLD management, as there is a lack of efficacious and safe pharmacotherapy for this disease.