Pomegranate juice flavonoids inhibit low-density lipoprotein oxidation and cardiovascular diseases: studies in atherosclerotic mice and in humans.

The beneficial health effects attributed to the consumption of fruit and vegetables are related, at least in part, to their antioxidant activity. Of special interest is the inverse relationship between the intake of dietary nutrients rich in polyphenols and cardiovascular diseases. This effect is attributed to polyphenols' ability to inhibit low-density lipoprotein (LDL) oxidation, macrophage foam cell formation and atherosclerosis. Pomegranate polyphenols can protect LDL against cell-mediated oxidation via two pathways, including either direct interaction of the polyphenols with the lipoprotein and/or an indirect effect through accumulation of polyphenols in arterial macrophages. Pomegranate polyphenols were shown to reduce the capacity of macrophages to oxidatively modify LDL, due to their interaction with LDL to inhibit its oxidation by scavenging reactive oxygen species and reactive nitrogen species and also due to accumulation of polyphenols in arterial macrophages; hence, the inhibition of macrophage lipid peroxidation and the formation of lipid peroxide-rich macrophages. Furthermore, pomegranate polyphenols increase serum paraoxonase activity, resulting in the hydrolysis of lipid peroxides in oxidized lipoproteins and in atherosclerotic lesions. These antioxidative and antiatherogenic effects of pomegranate polyphenols were demonstrated in vitro, as well as in vivo in humans and in atherosclerotic apolipoprotein E deficient mice. Dietary supplementation of polyphenol-rich pomegranate juice to atherosclerotic mice significantly inhibited the development of atherosclerotic lesions and this may be attributed to the protection of LDL against oxidation.

Pomegranate juice consumption inhibits serum angiotensin converting enzyme activity and reduces systolic blood pressure.

Consumption of pomegranate juice which is rich in tannins, possess anti-atherosclerotic properties which could be related to its potent anti-oxidative characteristics. As some antioxidants were recently shown to reduce blood pressure, we studied the effect of pomegranate juice consumption (50 ml, 1.5mmol of total polyphenols per day, for 2 weeks) by hypertensive patients on their blood pressure and on serum angiotensin converting enzyme (ACE) activity. A 36% decrement in serum ACE activity and a 5% reduction in systolic blood pressure were noted. Similar dose-dependent inhibitory effect (31%) of pomegranate juice on serum ACE activity was observed also in vitro. As reduction in serum ACE activity, even with no decrement in blood pressure, was previously shown to attenuate atherosclerosis, pomegranate juice can offer a wide protection against cardiovascular diseases which could be related to its inhibitory effect on oxidative stress and on serum ACE activity.

Pomegranate juice supplementation to atherosclerotic mice reduces macrophage lipid peroxidation, cellular cholesterol accumulation and development of atherosclerosis.

Inhibition of lipid peroxidation contributes to the attenuation of macrophage cholesterol accumulation, foam-cell formation and atherosclerosis. Evidence suggests that nutritional antioxidants such as pomegranate juice (PJ) can contribute to the reduction of oxidative stress and atherogenesis. The goals of the present study were to determine whether such beneficial effects of PJ exist when supplemented to apolipoprotein E-deficient (E(0)) mice with advanced atherosclerosis and to analyze the antiatherosclerotic activity of a tannin-fraction isolated from PJ. Mice (4-mo-old) were supplemented with PJ in their drinking water for 2 mo and compared with age-matched placebo-treated mice, as well as to young (4-mo-old) control mice, for their mouse peritoneal macrophage (MPM) oxidative state, cholesterol flux and mice atherosclerotic lesion size. PJ supplementation reduced each of the proatherogenic variables determined in the present study compared with age-matched placebo-treated mice. It significantly induced serum paraoxonase activity and reduced MPM lipid peroxide content compared with placebo-treated mice and control mice. PJ administration to E(0) mice significantly reduced the oxidized (Ox)-LDL MPM uptake by 31% and MPM cholesterol esterification and increased macrophage cholesterol efflux by 39% compared with age-matched, placebo-treated mice. PJ consumption reduced macrophage Ox-LDL uptake and cholesterol esterification to levels lower than those in 4-mo-old, unsupplemented controls. PJ supplementation to E(0) mice with advanced atherosclerosis reduced the lesion size by 17% compared with placebo-treated mice. In a separate study, supplementation of young (2-mo-old) E(0) mice for 2 mo with a tannin fraction isolated from PJ reduced their atherosclerotic lesion size, paralleled by reduced plasma lipid peroxidation and decreased Ox-LDL MPM uptake. PJ supplementation to mice with advanced atherosclerosis reduced their macrophage oxidative stress, their macrophage cholesterol flux and even attenuated the development of atherosclerosis. Moreover, a tannin-fraction isolated from PJ had a significant antiatherosclerotic activity.

Pomegranate juice consumption reduces oxidative stress, atherogenic modifications to LDL, and platelet aggregation: studies in humans and in atherosclerotic apolipoprotein E-deficient mice.

BACKGROUND: Dietary supplementation with nutrients rich in antioxidants is associated with inhibition of atherogenic modifications to LDL, macrophage foam cell formation, and atherosclerosis. Pomegranates are a source of polyphenols and other antioxidants. OBJECTIVE: We analyzed, in healthy male volunteers and in atherosclerotic apolipoprotein E-deficient (E(0)) mice, the effect of pomegranate juice consumption on lipoprotein oxidation, aggregation, and retention; macrophage atherogenicity; platelet aggregation; and atherosclerosis. DESIGN: Potent antioxidative effects of pomegranate juice against lipid peroxidation in whole plasma and in isolated lipoproteins (HDL and LDL) were assessed in humans and in E(0) mice after pomegranate juice consumption for

Dietary restriction on serum thyroid hormone levels.

To determine the long term effects of a protein sparing fast on serum thyroid hormone levels, the authors studied 38 obese patients ingesting a diet of 320 kcal for up to 13 weeks. The high baseline serum triiodothyronine (T3) levels decreased significantly by the first week, further decreased by the third week, and this lower level persisted for the duration of the fast until realimentation. Serum free T3 index followed the same general pattern as did serum T3 levels. Serum reverse T3 increased significantly by the first week, but by week three, the reverse T3 level had begun to fall, although still significantly increased above baseline. By week seven, reverse T3 had decreased to almost baseline and remained not significantly changed from the baseline to 13 weeks. Serum thyroxine (T4) increased significantly by the first week in all patients, but by the third week had returned to baseline levels which persisted to 13 weeks. The free T4 index and free T4 concentrations showed the same increment at week one and then returned to baseline levels. There were no significant changes in serum thyroxine-binding globulin (TBG) or thyroid-stimulating hormone (TSH) concentrations. The changes in serum T3 and reverse T3 levels are attributable to alterations in peripheral 5'-monodeiodination of T4 and reverse T3 induced by the protein sparing fast.

Mechanisms of hypertension in obesity.

We conclude that the following may explain the rise in blood pressure with obesity and the subsequent fall in blood pressure (Fig. 2): (1) An increase in calories, protein, or carbohydrate leads to an increase in plasma catecholamines, sympathetic nervous system activity, and insulin secretion. (2) These factors, in turn, lead to increased renal sodium retention and stimulation of the renin-aldosterone system which, in turn, leads to: (3) An increased cardiac output with an inability to appropriately adjust the peripheral resistance to maintain normotension with resultant hypertension. Conversely, the fall in blood pressure with weight reduction can be explained by (Fig. 3): (1) A decrease in calorie, carbohydrate, or protein intake which leads to: (2) A decrease in circulating plasma catecholamines, sympathetic nervous system activity, and insulin secretion which results in: (3) A natriuresis and decrease in the renin-aldosterone system, which causes a decrease in circulating blood volume and in cardiac output. This, in turn, lowers blood pressure towards normal. The unanswered question still remains: why do some obese patients become hypertensive and others remain normotensive? Perhaps there are weight-sensitive individuals and weight-resistant individuals just as there appear to be salt-sensitive and salt-resistant hypertensive patients. Perhaps the answer is genetic. These questions also remain to be answered.

Obesity and hypertension: long-term effects of weight reduction on blood pressure.

Long-term follow-up studies were conducted on massively obese hypertensive subjects during and after a successful protein supplemented fast (PSMF) in order to correlate blood pressure changes with caloric intake and body weight. The blood pressures in 43 subjects were compared during rapid weight loss and at identical weights during post-fast weight gain (Study A). Blood pressures and body weights in 50 subjects were compared prior to starting PSMF and prior to restarting the program 21 months later (Study B). One hundred twenty-five compliant subjects were observed after one month of weight maintenance (Study C-1), and 39 subjects were followed during six months of weight maintenance (Study C-2). In Study A, during subsequent weight gain on an unrestricted diet blood pressure was significantly higher than at identical weight during continuous weight loss on PSMF. However, this increase in blood pressure was only approximately 30 percent of the original decrease. In Study B, weight loss and blood pressure reduction were significantly correlated. After one month of weight maintenance following continuous weight loss of 73 lb, there was no increase in blood pressure (Study C-1). A small but significant increase in blood pressure after six months (Study C-2) was associated with similar small weight increment. However, all blood pressures remained well within the normotensive range and significantly lower than control values. In this study, long-term changes in blood pressure correlated with changes in body weight.

Defective renal prostaglandin synthesis in hypertensive patients with morbid obesity.

Renal prostaglandin synthesis in 36 obese hypertensive patients was estimated from measurements of 24-hour urinary prostaglandin E2 (PGE2) excretion rates. PGE2 was measured by radioimmunoassay using Dray antiserum prior to and 1 week after starting a fast supplemented by 320 cal derived from 30 g of carbohydrate, 45 g protein, and 2 g essential fatty acids. Sodium intake was 120 mEq daily or less. Comparisons were made to a control population of age-matched, nonobese, normotensive, healthy volunteers on a normal diet. Mean weight fell from 260 +/- 8 to 247 +/- 8lb, p less than 0.001. Urinary PGE2 in the obese patients prior to the fast was 104 +/- 27 ng/day, significantly lower than the 404 +/- 124 ng/day found in the control population, p less than 0.005. After the 1st week of the fast urinary PGE2 rose to 213 +/- 55, p less than 0,02. This value was not different from that in the control group. Blood pressure fell (p less than 0.001) in these patients from 143/94 +/- 3/2 to 134/87 +/- 3/2 mm Hg after the 1st week of the fast. Deficient renal prostaglandin synthesis in obese hypertensive patients was corrected by fasting. Such changes in the prostaglandin system may mediate or occur in response to changes in the sodium-volume balance of these patients. These changes in renal prostaglandin synthesis may partly contribute to the blood pressure reduction of these patients.

BP changes in obese hypertensive subjects during rapid weight loss. Comparison of restricted v unchanged salt intake.

A controlled prospective study compared two groups of obese hypertensive subjects during 12 weeks of a hypocaloric protein-supplemented fast containing 40 mEq of sodium daily. One group received additional sodium chloride sufficient to maintain baseline sodium intake measured prior to the fast (210 m/Eq/day). Sodium restriction resulted in greater weight loss and slightly greater BP reduction only during the initial week of fasting. Thereafter, despite sodium equilibrium, further substantial weight loss and BP reduction were identical in both groups, the decrement in weight being linear (1.89 kg/wk) and the BP reduction asymptotic. Although the initial reduction in BP during the first week of supplemented fast may be attributable to negative salt and water balance, the further reduction in BP during a period of constant sodium balance must be caused by weight loss per se or by the triggering of other antihypertensive mechanisms associated with weight reduction.

A comprehensive psychological approach to obesity.

Many different treatments for obesity have proven somewhat successful, with none emerging as clearly superior to the others. Surgical approaches, although usually successful at achieving and maintaining weight loss, are accompanied by varied and often harmful side effects. Unless new, safer procedures are developed, treatment may continue to be as hazardous as the obesity itself. Because medical treatment alone has not achieved beneficial, lasting results, research aimed at finding new procedures should be encouraged. Our five-year experience in working with obese patients has led us to the following conclusions: 1. The management of obesity must be a joint venture between psychiatry and medicine. Because of the complex nature of this illness, neither discipline alone can successfully and safely achieve significant initial weight loss coupled with successful long-term maintenance. The use of adjunctive psychological programs in a medical setting can be a successful alternative. 2. Fasting, weight loss, and realimentation must be accompanied by an effort at lifestyle change. Otherwise, patients will continue their self-destructive habits, which will ultimately lead to failure in yet another attempt at sustained weight reduction. The behavioral approach has provided a fairly effective treatment of obesity, sometimes with immediate results. Recent studies support the maintenance effect of behavioral treatments. However, longer studies with follow-ups are needed to better assess the overall effectiveness of these treatments. 3. Despite much false optimism that weight loss is a simple road to happiness, most patients experience some very real problems during the fasting part of the program. Crisis intervention can prove very helpful in terms of reducing stress and preventing dropouts. Group therapy, individual therapy, family therapy, and hypnosis have attained some very limited positive results when used alone; greater success has been reported from combining therapies. Patients generally became more socially effective, physically active, and mentally proficient when exposed to individual therapy together with group and family therapies. 4. Family environment appears to significantly affect compliance and completion. A conflict-laden family environment hampers the patient's ability to deal with the psychological changes encountered in weight loss programs. 5. Many obese patients lack a fundamental knowledge of nutrition, exercise, and health. In addition, most are poorly socialized and require assistance in learning assertiveness and other interpersonal skills. A behaviorally oriented component is very effective in providing these skills.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of weight loss on the dexamethasone suppression test.

The authors studied postdexamethasone cortisol secretion in 18 depression-free, healthy, obese subjects before and after weight loss. Although all subjects suppressed cortisol normally before weight loss, 5 of 18 (27.5%) failed to suppress cortisol after an average loss of 13.5 kg. This failure to suppress cortisol was not associated with any change in depression ratings.

Error in blood-pressure measurement due to incorrect cuff size in obese patients.

Trained nurse-specialists obtained 84 000 blood-pressure measurements in 1240 obese subjects using cuffs of the three standard adult sizes in a randomised order. The differences in readings between the three cuffs were smallest in non-obese subjects and became progressively greater with increasing arm circumference (AC) in the obese population. The regular cuff (12 X 23 cm) showed the greatest bias in relation to AC. Formulae and a table have been derived to correct the measurement error caused by cuffs of inappropriate size at various ACs. The reported high prevalence of hypertension in obese subjects may be greatly overestimated.

Role of the sympathetic nervous system in blood pressure maintenance in obesity.

A group of 10 borderline hypertensive obese subjects had higher (P less than 0.05) supine plasma norepinephrine (NE), epinephrine, and PRA levels as well as greater (P less than 0.05) NE responses to upright posture and isometric handgrip exercise than 12 nonobese controls. Plasma NE as well as mean arterial pressure (MAP) responses to posture and handgrip in the obese patients demonstrated a significant decrement at week 2 after the onset of a low calorie diet. Decrements in plasma NE and MAP responses to posture were correlated (r = 0.61; P less than 0.05) throughout an 8-week period of weight loss in these borderline hypertensive obese subjects. In 15 normotensive obese subjects as well as in the 10 borderline hypertensive obese subjects, weight reduction associated with a very low calorie intake was accompanied by a reduction in supine plasma NE, epinephrine, and MAP 2 weeks after the onset of dieting. PRA decreased after 8 weeks of dieting in both obese groups, and these PRA decrements were correlated with reductions in MAP and decrements in plasma NE. We conclude that enhanced sympathetic activity may play a role in the maintenance of elevated blood pressure in obese individuals. Decreases in PRA and blood pressure associated with weight loss in both normotensive and hypertensive obese individuals occurs, in part, secondary to reductions in plasma NE levels.

The effect of weight loss on reproductive hormones in obese men.

The effects of weight reduction on reproductive hormones were investigated in 24 moderately obese men, 18-108% above ideal body weight. Serum estrone (E1), estradiol (E2), testosterone (T), percent free T (%FT), sex hormone binding globulin (SHBG) capacity, and, in 9 subjects, androstenedione (A) were measured serially before and during an outpatient supplemented fasting program (320 kcal/day) for 8-20 weeks. In the baseline state mean E1 was elevated to 100 +/- 7 pg/ml (normal, 30-60 pg/ml). The E2 was slightly elevated to 36 +/- 3 pg/ml (normal, 8-35 pg/ml). The mean T of 400 +/- 20 ng/dl was at the lower end of normal (400-1000 ng/dl). The mean %FT was elevated to 4.1 +/- 0.2% (normal 1.6-3%). The calculated free T was normal. The mean SHBG binding capacity was 0.99 +/- 0.05 micrograms dihydrotestosterone bound/dl (normal, 1.0-1.8 micrograms/dl). The mean A of 52 +/- 5.8 ng/dl was normal. These data were in accord with previous findings in much heavier men. Eight weeks of weight loss (mean, 19.5 kg) were associated with normalization of all the measured parameters. The mean E1 decreased to 48 +/- 23 pg/ml, E2 to 28 +/- 2.1 pg/ml. T increased to 536 +/- 35 pg/dl and %FT fell to 3.2 +/- 0.2%. Data on men remaining on the program for 16 or 20 weeks showed a continued fall of estrogens and stabilization of T and %FT. SHBG and A did not change significantly over the entire time period. In conclusion, increased circulating estrogens and reduced androgen binding were found in moderately obese men, which were completely corrected with weight loss.

The effect of weight reduction on blood pressure, plasma renin activity, and plasma aldosterone levels in obese patients.

We investigated the relation between changes in the renin-aldosterone axis and reduction in blood pressure in 25 obese patients placed on a 12-week reducing diet; sodium intake was either medium (120 mmol) or low (40 mmol). Plasma renin activity (PRA) declined with weight loss, so that by 12 weeks there was a significant decrease in PRA (P less than 0.01) as well as plasma aldosterone (P less than 0.05), regardless of sodium intake. Weight loss with low sodium intake was equal to that with medium intake. The reduction in PRA but not in aldosterone correlated with weight loss in both sodium-intake groups (r = 0.58). Mean arterial pressure fell significantly and equally in both groups, correlating with weight loss throughout the study (r = 0.56) and with PRA from the fourth through 12th weeks (r = 0.48) These results demonstrate that weight loss is accompanied by reductions in PRA and aldosterone; PRA reductions, irrespective of sodium intake, may contribute to the decline in blood pressure.

Renal damage with intestinal bypass.

Renal function and biopsies were studied in 18 patients, 7 to 108 months after intestinal bypass. Enteropathy was found in 12 and hyperoxaluria in 16. Every biopsy showed a type of focal interstitial nephritis, tubular atrophy, fibrosis, and glomerular hyalinization. Damage ranged from minimal to extensive and renal function from normal to end-stage failure. Tubular injury had resulted partly from oxalate deposits. However, in 10 patients no oxalate crystals were seen. In eight others, most of the damaged areas were remote from crystal deposits. Immunoglobulin M and C3 deposits, found in glomerular capillaries and the messangium in six of 11 specimens, and the presence of circulating immune complexes in five of 10 patients, in addition to the extraintestinal organ involvement, suggested immune complex mesangial injury as one factor in bypass nephropathy. With progressive impairment of renal function, a biopsy appears justified. If damage is significant, the bypass should be dismantled.