Overview of Curcumin and Piperine Effects on Glucose Metabolism: The Case of an Insulinoma Patient's Loss of Consciousness.

The hypoglycemic properties of curcumin supplements in therapeutic doses are well-known and may represent a useful tool for the treatment of chronic diseases such as metabolic syndrome, insulin resistance and type 2 diabetes. The poor bioavailability of curcumin can be improved with the concomitant administration of piperine, with no severe adverse effects on glycemia reported so far in the literature. In this article, we further discuss a previously reported case of a helicopter pilot, affected by grade I obesity who, under curcumin and piperine treatment, experienced a transient loss of consciousness (TLOC), during a low-altitude flight. This episode led to a diagnosis of insulinoma, previously asymptomatic. We hypothesized that the combined effects of curcumin and piperine might have caused a severe hypoglycemic episode and subsequent TLOC. Therefore, further studies should be conducted to evaluate the safety of curcumin and piperine supplementation in subjects with impaired glucose metabolism and insulin secretion.

Physical Activity in Healthcare Workers With Low Back Pain: Effects of the Back-FIT Randomized Trial.

OBJECTIVE: To evaluate the effects of physical activity program in healthcare workers with low back pain (LBP). METHODS: A group of healthcare workers participated voluntarily to a meeting about LBP and to be accepted, were randomly allocated to workplace program or to home-based exercises, illustrated in a booklet and in a video available on the company intranet website. Both programs consisted in 7 weeks of moderate intensity exercises adapted to LBP. RESULTS: Most outcomes improved in both groups, however with larger improvement of the Oswestry Disability Index in the workplace group (P = 0.02). CONCLUSIONS: Regular physical exercise, at home or at the workplace among healthcare workers with LBP, represents a great opportunity to improve health and reduce disability.

L-arginine, asymmetric dimethylarginine, and symmetric dimethylarginine in plasma and synovial fluid of patients with knee osteoarthritis.

BACKGROUND: The aim of this study was to investigate the involvement of the nitric oxide (NO) pathway in osteoarthritis (OA). MATERIAL AND METHODS: The study groups consisted of 32 patients with knee OA and 31 healthy controls. In peripheral venous blood samples (from the OA patients and the controls) and in synovial fluid samples (from the OA patients), the concentrations of L-arginine (ARN), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) were evaluated. In plasma samples, thiobarbituric acid reactive substances (TBARS) were also measured. RESULTS: Plasma ARN concentrations were lower in the OA patients than in controls (53.55 ± 16.37 vs. 70.20 ± 25.68 µmol/l) (P<0.05), while plasma ADMA concentrations were similar. Accordingly, the ARN/ADMA ratio was lower in the OA patients than in the control group (80.85 ± 29.58 vs. 110.51 ± 30.48, P<0.05). Plasma SDMA and TBARS concentrations were higher in the OA patients than in controls (0.69 ± 0.15 vs. 0.60 ± 0.10 µmol/l, P<0.05 and 1.21 ± 0.29 vs. 0.55 ± 0.12, respectively) (P<0.001). In the OA patients, ADMA concentrations were significantly higher in the synovial fluid than in plasma (0.75 ± 0.09 vs. 0.69 ± 0.14 µmol/l, P<0.05), as were ARN concentrations (76.96 ± 16.73 vs. 53.55 ± 16.73 µmol/l) (P<0.00001). Conclusions These results indicate a poor availability of NO in the synovial fluid of the OA patients, which may contribute to the progression of OA. The decreased ARN/ADMA ratio and the increased SDMA and TBARS in the plasma of the OA patients suggest an impairment of endothelial function in these subjects.

Cardiovascular injury in systemic autoimmune diseases: an update.

It is well known in literature that systemic autoimmune diseases (SADs) are associated with enhanced atherosclerosis and impaired endothelial function early after the onset of the disease. Cardiovascular (CV) disease represents one of the leading causes of morbidity and mortality in SADs. There is considerable evidence suggesting a pathogenetic role of chronic inflammation and immune dysregulation for enhanced atherosclerosis in SADs, as demonstrated in several recent studies. Moreover, chronic inflammation, accelerated atherosclerosis and functional abnormalities of the endothelium suggest a subclinical CV involvement beginning rapidly soon after the onset of the disease and progressing with disease duration.

Coronary flow reserve and asymmetric dimethylarginine levels: new measurements for identifying subclinical atherosclerosis in patients with psoriatic arthritis.

OBJECTIVE: To identify the presence of subclinical atherosclerosis in patients with psoriatic arthritis (PsA) and healthy controls using intima-media thickness (IMT), coronary flow reserve (CFR), and the plasma concentration of asymmetric dimethylarginine (ADMA), to evaluate the correlations among ADMA, IMT, and CFR. METHODS: The study involved 22 patients who fulfilled the ClASsification of Psoriatic ARthritis study group criteria for PsA and a cohort of 35 healthy controls with no history or current signs of coronary artery disease (CAD). Common carotid IMT was measured using high-resolution B-mode ultrasonography. Dipyridamole transthoracic stress echocardiography was used to evaluate CFR. Blood samples were obtained to assess ADMA levels. The clinical manifestations were recorded. All patients were treated with disease-modifying antirheumatic drug, but none had received any biological or steroid therapy. RESULTS: Plasma ADMA levels were significantly higher in the patients with PsA (0.71 ± 0.07 µmol/l vs 0.48 ± 0.07 µmol/l; p = 0.00) and CFR was significantly reduced in that group (2.86 ± 0.70 vs 3.3 ± 0.43; p < 0.01) compared to controls. Common carotid IMT was greater in the patients with PsA, but the difference was not significant (0.64 ± 0.26 mm vs 0.62 ± 0.5 mm; p = 0.65). There was a significant correlation between CFR and plasma ADMA levels in the PsA group (R = 0.28; p < 0.01), but no correlation between plasma ADMA levels and IMT (R = 0.02; p = 0.32), Disease Activity Score 28 (p = 0.52), or Psoriasis Area and Severity Index (p = 0.98). CONCLUSION: Our patients with PsA showed a profile of subclinical atherosclerosis. ADMA may be a useful marker of endothelial dysfunction in PsA.

Robotic treadmill training improves cardiovascular function in spinal cord injury patients.

BACKGROUND: Body weight supported treadmill training (BWSTT) assisted with a robotic driven gait orthosis (DGO) is an emerging tool in rehabilitating patients with lost sensorimotor function. Few information about the effects of BWSTT on cardiovascular system are available. The purpose of this study was to determine the effects of BWSTT on: 1) left ventricular (LV) systo-diastolic function; 2) coronary flow reserve (CFR); 3) endothelial function in patients with lost sensorimotor function due to neurologic lesions. METHODS: Fourteen adults (males 10, age 50.6±17.1years) with motor incomplete spinal cord injuries (SCI) due to trauma or spondylotic diseases underwent standard echocardiographic examination, non invasive assessment of CFR by dipyridamole stress echo and determination of plasma asymmetric dimethylarginine (ADMA) levels at baseline and after 6weeks of BWSTT. RESULTS: At post training evaluation we observed lower LV end-diastolic (P=0.0164) and end-systolic volumes (P=0.0029) with increased ejection fraction (EF) (P=0.0266). We also observed a LV interventricular septum (IVS) (P=0.00469) increase. At the same time, we detected an improvement of LV diastolic function as witnessed by the reduction of isovolumic relaxation time (IVRT) (P=0.0404) and deceleration time (DT) (P=0.0405) with an increased E/A ratio (P=0.0040). Improved CFR (P=0.020) and reduced plasma ADMA levels (P=0.0005) have been observed too, in association with a reduction of the inflammatory status (C-reactive protein (CRP) (P=0.0022) and erythrocyte sedimentation rate (ESR) (P=0.0005)). CONCLUSION: For the first time, this study demonstrated that 6weeks of BWSTT improved not only the sensorimotor function but also systo-diastolic LV function, CFR and endothelial dysfunction associated with a reduction of the inflammatory status in patients with incomplete SCI.

The heart in rheumatoid arthritis.

Morbidity and mortality rates are higher in rheumatoid arthritis (RA) patients than in the general population. Many studies have shown that coronary artery disease is one of the most common causes of death in RA and seems to occur at a younger age than in the general population. RA per se is as much a cardiovascular (CV) risk factor as diabetes, arterial hypertension and dyslipidemia etc., and so it is necessary to plan a follow-up using the same diagnostic and therapeutic approaches as those commonly used for primary and secondary prevention in non-RA patients at high CV risk. All of the cardiac structures can be affected during the course of RA (valves, the conduction system, the myocardium, endocardium and pericardium, and the coronary arteries), and cardiac complications include a variety of clinical manifestations. As these are all associated with an unfavourable prognosis, it is essential to detect subclinical cardiac involvement in still asymptomatic RA patients in order to assure adequate long-term treatment.

Non-invasive assessment of coronary flow reserve and ADMA levels: a case-control study of early rheumatoid arthritis patients.

OBJECTIVE: Plasma concentration of asymmetric dimethylarginine (ADMA), a major endogenous inhibitor of nitric oxide synthase, is considered a novel risk factor for endothelial dysfunction associated with enhanced atherosclerosis. Coronary microcirculation abnormalities have been demonstrated in patients with early rheumatoid arthritis (ERA) without any signs or symptoms of coronary artery disease (CAD). The aim of the study was to compare the ERA and control groups with ADMA, intima-media thickness (IMT) and coronary flow reserve (CFR) levels. It assessed whether ERA patients have more cardiovascular risk (endothelial dysfunction and coronary microvascular abnormalities), and evaluated whether any difference in IMT/CFR between ERA and controls can be explained by any difference in ADMA levels between the groups. METHODS: The study involved 25 ERA patients (female/male 21/4; mean age 52.04 +/- 14.05 years; disease duration

Asymmetric dimethylarginine (ADMA): an endogenous inhibitor of nitric oxide synthase and a novel cardiovascular risk molecule.

Asymmetric dimethylarginine (ADMA), a methyl derivate of the amino acid arginine, is produced by the physiological degradation of methylated proteins. ADMA is the major endogenous inhibitor of nitric oxide synthase (NOS), the enzyme which synthesizes nitric oxide (NO), a molecule endowed with important anti-atherosclerotic properties. Increased plasma ADMA concentrations cause impaired NO synthesis leading to endothelial dysfunction and atherosclerotic vascular disease. Increased plasma ADMA levels mainly occur following inhibition of the enzyme responsible for ADMA catabolism, dimethylarginine dimethylaminohydrolase (DDAH), by oxidative stress triggered by several cardiovascular risk factors. This paper reviews the effects on cardiovascular function produced by ADMA administration to experimental animals and humans. In addition, a number of clinical conditions associated with increased plasma ADMA concentrations are considered. Then the growing body of literature indicating that plasma ADMA levels have a predictive value for major cardiovascular events in prospective studies is discussed. Finally, an analysis is provided of the published data concerning the possibility to modulate plasma ADMA levels using drugs belonging to different pharmacological classes.

Cardiovascular involvement in systemic autoimmune diseases.

Autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), primary antiphospholipid syndrome (APS), systemic sclerosis and systemic vasculitis, affect a large number of people in whom one of the leading causes of morbidity and mortality is cardiovascular disease. Cardiovascular disease is associated with the development of accelerated atherosclerosis. It seems to occur at a younger age than in the general population, is often asymptomatic and, in addition to traditional risk factors, also involves specific risk factors as chronic inflammation, the duration and activity of the autoimmune disease, and immunosuppressive therapy. The early phases of cardiovascular involvement in patients with autoimmune diseases may be clinically silent, with only a microcirculation disorder present. There are various means of detecting morphological cardiac damage: coronary angiography remains the gold standard for diagnosing coronary stenosis, but new, non invasive and more reliable methods have been introduced into clinical practice in order to detect subclinical microcirculation abnormalities.

Asymmetric dimethylarginine (ADMA) induces vascular endothelium impairment and aggravates post-ischemic ventricular dysfunction in rats.

Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide (NO) inhibitor recognized as an independent risk factor for endothelial dysfunction and coronary heart diseases. This study investigated whether ADMA (10 mg/kg day for 14 days) affected endothelial function and aggravated post-ischemic ventricular dysfunction in the perfused rat heart. Systolic blood pressure and heart rate, plasma levels of ADMA and nitrite/nitrate were measured in vehicle- and ADMA-treated rats. Perfused hearts were submitted to global ischemia-reperfusion and vascular endothelial dysfunction was examined with angiotensin II in coronary vessels and aortic rings. Endothelial NO synthase (eNOS) and angiotensin-converting enzyme (ACE) mRNA expression in aortic and cardiac tissues were measured. ADMA-treated rats had higher systolic blood pressure (1.3-fold, P<0.01) and slower heart rate (16%, P<0.05) than controls. Plasma ADMA rose (1.9-fold, P<0.01) and nitrite/nitrate concentration decreased 59% (P<0.001). Ventricular contraction (stiffness) increased significantly, with worsening of post-ischemic ventricular dysfunction. In preparations from ADMA-treated rats the coronary vasculature's response to angiotensin II was almost doubled (P<0.01) and the maximal vasorelaxant effect of acetylcholine in aortic rings was significantly lower than in preparations from vehicle-treated rats. In cardiac and aortic tissues eNOS mRNA and ACE mRNA levels were similar in controls and ADMA-treated rats. The increased plasma levels of ADMA presumably cause endothelial dysfunction because of a deficiency in NO production, which also appears involved in the aggravation of myocardial ischemia-reperfusion injury.

Nitric oxide and prostacyclin pathways: an integrated mechanism that limits myocardial infarction progression in anaesthetized rats.

Nitric oxide (NO) and cyclooxygenase-derived prostaglandins, such as prostacyclin (PGI2), are involved in vascular homeostasis. To better understand the reciprocal role of both NO and PGI2 on myocardial infarction in the rat, we have investigated the cardioprotective effect of nitro-naproxen, isosorbide dinitrate (ISDN), L-arginine, defibrotide and naproxen. In this study, male Wistar rats were treated orally once a day for 5 consecutive days with the compounds under investigation and then, under anesthesia, the animals were subjected to acute myocardial ischemia (30 min) and reperfusion (120 min). Systemic blood pressure, left ventricular pressure and related parameters of cardiac mechanics were recorded. Ventricular arrhythmias and infarct size of the left ventricular wall were also evaluated. Furthermore, cardiac myeloperoxidase (MPO) and plasma creatine phosphokinase (CPK) activities were determined. Defibrotide, nitro-naproxen, ISDN and L-arginine all provided a cardioprotection characterized by significant prevention of arrhythmias with high survival rate of the rats. Infarct size restriction was paralleled by reduction of both cardiac MPO and plasma CK. Cardioprotection of nitro-naproxen, ISDN and L-arginine involve nitrites/nitrates and PGI2-increased in the circulation associated to a reduction of thromboxane B2 (TXB2) in the blood. Defibrotide displays a cardioprotection by increasing PGI2 release and by reducing TXB2 in the blood. Naproxen was devoid a lower protecting activity on myocardial infarction, and PGI2 inhibition may have played a critical role in this context. The results suggested that the increase of both NO and PGI2 brings about a cascade of integrated cellular and molecular events which are of paramount importance in prevention of myocardial ischemic insult.

Angiotensin II type 1 receptor antagonism improves endothelial vasodilator function in L-NAME-induced hypertensive rats by a kinin-dependent mechanism.

OBJECTIVE: This study was designed to investigate the ability of a chronic blockade of angiotensin II type 1 receptors with losartan to reverse the endothelial dysfunction present in N-nitro-L-arginine methyl ester (L-NAME)-treated hypertensive rats and the possible dependence of this effect on bradykinin B2-receptor activation. METHODS: Rats treated with L-NAME alone (60 mg/kg per day for 8 weeks) or with L-NAME + losartan, L-NAME + icatibant (a bradykinin B2-receptor antagonist) and L-NAME + losartan + icatibant were studied. Losartan, icatibant or losartan + icatibant were co-administered with L-NAME during the last 4 weeks of the experiment. Endothelial nitric oxide synthase gene expression in aortic tissues, plasma nitrite/nitrate concentrations, the relaxant effect of acetylcholine on norepinephrine-precontracted aortic rings and 6-keto-PGF1alpha release from aortic rings were used as markers of the endothelial function. RESULTS: Rats treated with L-NAME alone and L-NAME + icatibant showed, as compared with untreated animals, a clear-cut increase in systolic blood pressure and a decrease of all the markers of endothelial function evaluated. In L-NAME-rats, administration of losartan reduced the systolic blood pressure and restored endothelial nitric oxide synthase gene expression, plasma nitrite/nitrate levels, the relaxant activity of acetylcholine on aortic rings and the generation of 6-keto-PGF1alpha from the aortic tissues. Co-administration of icatibant with losartan blunted the stimulatory effect of losartan on the markers of endothelial function evaluated. CONCLUSION: These results demonstrated that losartan is capable of reversing the endothelial vasodilator dysfunction in L-NAME-induced hypertensive rats, and that the beneficial effect of losartan is mediated by bradykinin B2-receptor activation.

Angiotensin-converting enzyme inhibition and angiotensin AT1-receptor antagonism equally improve endothelial vasodilator function in L-NAME-induced hypertensive rats.

Male Sprague-Dawley rats given N(omega)-nitro-L-arginine methyl ester (L-NAME) in drinking water for 8 weeks showed: (1) a clear-cut increase in systolic blood pressure; (2) a consistent decrease of endothelial-cell nitric oxide synthase (eNOS) gene expression in aortic tissue; (3) a marked reduction of plasma nitrite/nitrate concentrations; (4) a reduction of the relaxant activity of acetylcholine (ACh, from 10(-10) to 10(-4) M) on norepinephrine-precontracted aortic rings (reduction by 48+/-5%); (5) a marked decrease (-58%) of the basal release of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) from aortic rings. In L-NAME-treated rats, administration in the last 4 weeks of either the angiotensin-converting enzyme (ACE) inhibitor enalapril (10 mg/kg/day in tap water) or the angiotensin AT(1)-receptor antagonist losartan (10 mg/kg/day in tap water) decreased systolic blood pressure levels, completely restored eNOS mRNA levels in aortic tissue and plasma nitrite/nitrate levels, and allowed a consistent recovery of both the relaxant activity of acetylcholine and the generation of 6-keto-PGF1alpha. Coadministration of icatibant, a bradykinin B(2)-receptor antagonist (200 microg/kg/day), with enalapril blunted the stimulatory effect of the ACE inhibitor on eNOS mRNA expression, circulating levels of nitrite/nitrate, the relaxant activity of ACh and the release of 6-keto-PGF1alpha in L-NAME-treated rats. The generation of 6-keto-PGF1alpha from aortic rings was also decreased in rats coadministered icatibant with losartan. These findings indicate that (1) the ACE inhibitor enalapril and the angiotensin AT(1)-receptor blocker losartan are equally effective to reverse NAME-induced endothelial dysfunction; (2) the beneficial effect of enalapril on the endothelial vasodilator function in L-NAME-treated rats is mediated by bradykinin B(2)-receptor activation; and (3) the enhanced endothelial generation of prostacyclin induced by losartan in L-NAME rats is also mediated by bradykinin B(2)-receptor activation.

Enalapril and quinapril improve endothelial vasodilator function and aortic eNOS gene expression in L-NAME-treated rats.

Endothelial dysfunction ensuing inhibition of nitric oxide synthase (NOS) was investigated in male Sprague-Dawley rats given N(omega)-nitro-L-arginine methyl ester (L-NAME) in drinking water for 8 weeks. Age-matched rats served as controls. L-NAME-treated rats, as compared to control animals, showed: (1) a clear-cut increase in systolic blood pressure; (2) a consistent decrease of endothelial-cell NOS (eNOS) gene expression in aortic tissue; (3) a reduction of the relaxant activity of acetylcholine (ACh, from 10(-10) to 10(-4) M) on norepinephrine-precontracted aortic rings (reduction by 52+/-5%); (4) a marked decrease (-50%) of the basal release of 6-keto-prostaglandin F(1 alpha) (6-keto-PGF(1 alpha)) from aortic rings. In L-NAME-treated rats, administration in the last 2 weeks of either the angiotensin-converting enzyme inhibitor enalapril (1 mg/kg/day) or the cognate drug quinapril (1 mg/kg/day) decreased systolic blood pressure levels, completely restored eNOS mRNA levels in aortic tissue, and allowed a consistent recovery of both the relaxant activity of ACh and the generation of 6-keto-PGF(1 alpha). No difference was present in the ability of the two angiotensin-converting enzyme inhibitors to reverse NAME-induced endothelial dysfunction. These findings indicate that L-NAME-induced hypertension in the rat relies on the marked impairment of the endothelial vasodilator function, with an ensuing contribution by a decreased production of prostacyclin by the endothelial cells. Angiotensin-converting enzyme inhibition by enalapril or quinapril was equally effective in improving endothelial vasodilator function, prostacyclin endothelial production and restoring aortic eNOS mRNA.