A proprietary herbal extract titred in verbascoside and aucubin suppresses lipopolysaccharide-stimulated expressions of cyclooxygenase-2 in human neutrophils.

INTRODUCTION: Bacterial lipopolysaccharide (LPS) initiates several major cellular responses that play a crucial role in the pathogenesis of inflammation, including activation of neutrophils and production of prostaglandin E2 (PGE2) by cyclooxygenase-2 (COX-2). MATERIAL AND METHODS: Recent years have witnessed a growing interest in natural compounds as promising alternatives to synthetic COX-2 inhibitors. In this study, we sought to investigate the effect of a proprietary herbal extract from Lippia citriodora and Plantago lanceolata, titred in verbascoside (≥ 5%) and aucubin (≥ 2%), against LPS-stimulated expressions of COX-2 in human neutrophils using both reverse transcription-polymerase chain reaction (RT-PCR) and a PGE2 immunoassay. RESULTS: Our main results indicated that: 1. The proprietary herbal extract titred in verbascoside and aucubin is not significantly cytotoxic as shown by the MTT assay; 2. The extract does not significantly inhibit COX-1, whereas it is able to suppress LPS-elicited COX-2 hyperexpression at the mRNA level in human neutrophils; and 3. The effect of the extract at 5% concentration was comparable to that elicited celecoxib 1%, although, in terms of absolute and relative reduction of COX-2 mRNA expression and production of PGE2 in human neutrophils, the drug significantly outperformed the extract. CONCLUSIONS: In general, these results suggest that the proprietary herbal extract titred in verbascoside and aucubin is safe and may possess significant anti-inflammatory and analgesic effects by acting as a specific COX-2 inhibitor. Further studies are required to confirm the clinical efficacy of the extract.

Effects of a nutraceutical combination of fermented red rice, liposomal berberine, and curcumin on lipid and inflammatory parameters in patients with mild-to-moderate hypercholesterolemia: an 8-week, open-label, single-arm pilot study.

INTRODUCTION: The present open-label, single-arm pilot study sought to evaluate the effects of a nutraceutical combination containing fermented red rice, liposomal berberine, and curcumin on lipid and inflammatory parameters in patients with mild-to-moderate hypercholesterolemia. MATERIAL AND METHODS: Forty patients with mild-to-moderate hypercholesterolemia received the nutraceutical combination containing fermented red rice, liposomal berberine, and curcumin, once a day for 8 weeks. The study outcomes included changes from baseline in lipid (total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), oxidized low-density lipoprotein (oxLDL), high-density-lipoprotein cholesterol (HDL-C), and triglycerides (TG)) and inflammatory parameters (high-sensitivity C-reactive protein (hs-CRP) and tumor necrosis factor-α (TNF-α)). RESULTS: Compared with baseline, the nutraceutical combination produced a statistically significant reduction of TC (-20.4%, p < 0.05), LDL-C (-27.6%, p < 0.05), oxLDL (-23.2%, p < 0.05), and TG (-17.9%, p < 0.05). We also observed a reduction from baseline for hs-CRP (-15.4%, p < 0.05) and TNF-α (-14.3%, p < 0.05). The treatment was well tolerated and none of the patients discontinued treatment due to adverse effects. No cases of myalgia or musculoskeletal system disorders were observed. CONCLUSIONS: The nutraceutical combination of fermented red rice, liposomal berberine, and curcumin improves lipid profile and reduces markers of inflammation in low-risk dyslipidemic patients, with potential implications for primary prevention of cardiovascular disease.

Comparative effects of a fixed Polypodium leucotomos/Pomegranate combination versus Polypodium leucotomos alone on skin biophysical parameters.

OBJECTIVES: Polypodium leucotomos extract is a commonly used systemic photoprotective agent. In an exploratory fashion, the current study aimed to compare the effects of oral supplementation with a fixed Polypodium leucotomos/pomegranate combination (PPmix®) versus Polypodium leucotomos alone (Fernblock®) on skin biophysical parameters of Caucasian adults. METHODS: Forty healthy adult volunteers (20 males and 20 females; mean age: 37.2±5.5 years) were randomized in a 1:1 fashion to a fixed Polypodium leucotomos/pomegranate combination (480 mg/day; n=20) or Polypodium leucotomos alone (480 mg/day; n=20) for 3 months. Six skin biophysical parameters (skin sebum content, hydration, transepidermal water loss [TEWL], erythema index, melanin index, and elasticity) were measured at baseline and after 3 months by personnel blinded to participant allocation. RESULTS: At the end of the study, hydration and elasticity were significantly improved and TEWL was reduced in both groups, without significant intergroup differences. The erythema index was decreased by both treatments, although the fixed Polypodium leucotomos/pomegranate combination was significantly more effective. Finally, melanin index and skin sebum content were reduced by the fixed Polypodium leucotomos/pomegranate combination, whereas Polypodium leucotomos alone did not affect them. CONCLUSIONS: Our results suggest that a fixed Polypodium leucotomos/pomegranate combination provides a greater improvement of skin biophysical parameters compared to Polypodium leucotomos alone in adult Caucasians. Our findings may have implications for optimizing systemic skin photoprotection and beautification strategies.

Baicalin supplementation reduces serum biomarkers of skeletal muscle wasting and may protect against lean body mass reduction in cancer patients: Results from a pilot open-label study.

OBJECTIVES: Muscle wasting in patients with cancer has been linked to an increased activity of nuclear factor κB (NF-κB) and higher circulating levels of activin-A (ActA), a negative growth factor for muscle mass. Baicalin is a natural flavonoid that can reduce skeletal muscle atrophy in animal models of cancer cachexia by inhibiting NF-κB. This pilot open-label study assessed the effects of baicalin supplementation (50 mg daily for 3 months) in cancer patients who showed involuntary weight loss >5% over the past 6 months. METHODS: A total of 20 patients were investigated. Participants were evaluated at baseline and at the end of the 3-month study period for the following endpoints: 1) changes from baseline in serum NF-κB and ActA levels; and 2) change from baseline in lean body mass (LBM). RESULTS: We observed significant reduction in both NF-κB (p<0.05) and ActA (p<0.05) serum levels from baseline to 3 months. At 3 months, patients also showed a significant mean increase in LBM (+0.8 kg, p<0.05 compared with baseline). CONCLUSION: Our pilot open-label data suggest that baicalin supplementation is potentially useful for contrasting lean body mass reduction in cancer patients with involuntary weight loss, an effect which is likely mediated by the inhibition of negative growth factors for muscle mass.

Protective effect of trehalose-loaded liposomes against UVB-induced photodamage in human keratinocytes.

Trehalose, a naturally occurring non-reducing disaccharide, is known to act as a major protein stabilizer that can reduce ultraviolet B (UVB)-induced corneal damage when topically applied to the eye. However, due to the low skin permeability of trehalose, which makes the development of topical formulations difficult, its use as a skin photoprotective agent has been limited. Previous findings demonstrated that liposomes may significantly improve the intracellular delivery of trehalose. Therefore, the present study aimed to assess the protective effects of trehalose-loaded liposomes against UVB-induced photodamage using the immortalized human keratinocyte cell line, HaCaT. The effects were also compared to those of the common skin photoprotective compounds, including L-carnosine, L-(+)-ergothioneine, L-ascorbic acid and DL-α-tocopherol. The levels of cyclobutane pyrimidine dimers, 8-hydroxy-2'-deoxyguanosine and protein carbonylation in HaCaT cells were used as biological markers of UVB-induced damage. Compared to other compounds, trehalose-loaded liposomes showed the highest efficacy in reducing the levels of the three markers following UVB irradiation of HaCaT cells (all P<0.001 when compared to each of the four other photoprotective compounds). Therefore, these findings indicate that there may be a clinical application for trehalose-loaded liposomes, and further studies should be performed to assess the potential usefulness in skin photoprotection and the prevention of non-melanoma skin cancer.

Anti-inflammatory effects of a topical preparation containing nicotinamide, retinol, and 7-dehydrocholesterol in patients with acne: a gene expression study.

PURPOSE: Acne vulgaris is a skin disorder of the sebaceous follicles, involving hyperkeratinization and perifollicular inflammation. Aberrant extracellular matrix remodeling due to matrix metalloproteinases (MMPs) has been associated with the presence of acne conditions. Given the complex pathophysiology of acne, novel topical therapies should include combination products that target multiple pathogenetic mechanisms. In this pilot study we investigated the changes in gene expression of extracellular MMPs, the tissue inhibitors of metalloproteinases, and proinflammatory molecules after 45 days of topical application of a combination product containing nicotinamide, retinol, and 7-dehydrocholesterol in 16 patients with inflammatory acne on their back. MATERIALS AND METHODS: Skin biopsies were obtained before and after treatment for gene expression studies. RESULTS: Quantitative real-time polymerase chain reaction revealed a significant downregulation of MMP-1, MMP-2, MMP-9, MMP-14, interleukin-6, monocyte chemoattractant protein-1, and macrophage migration inhibitory factor. In contrast, the tissue inhibitors of metalloproteinases and transforming growth factor-ß1 were significantly upregulated. The gene expression findings correlated well with the clinical treatment response. CONCLUSIONS: The combination of nicotinamide, retinol, and 7-dehydrocholesterol appears to be effective for acne treatment from both clinical and molecular standpoints.

Reduced ultraviolet-induced DNA damage and apoptosis in human skin with topical application of a photolyase-containing DNA repair enzyme cream: clues to skin cancer prevention.

The exposure of human skin to ultraviolet radiation (UVR) results in the formation of DNA photolesions that give rise to photoaging, mutations, cell death and the onset of carcinogenic events. Photolyase (EC 4.1.99.3) is a DNA repair enzyme that reverses damage caused by exposure to UVR. We sought to investigate whether addition of photolyase enhances the protection provided by a traditional sunscreen (SS), by reducing the in vivo formation of cyclobutane-type pyrimidine dimers (CPDs) and UVR-induced apoptosis in human skin. Ten volunteers (Fitzpatrick skin type II) were exposed to solar-simulated (ss) UVR at a three times minimal erythema dose for 4 consecutive days. Thirty minutes prior to each exposure, the test materials [vehicle, SS (sun protection factor 50) alone, and SS plus photolyase from Anacystis nidulans] were applied topically to three different sites. One additional site was left untreated and one received ssUVR only. Biopsy specimens were taken 72 h after the last irradiation. The amount of CPDs and the extent of apoptosis were measured by ELISA. Photolyase plus SS was superior to SS alone in reducing both the formation of CPDs and apoptotic cell death (both P<0.001). In conclusion, the addition of photolyase to a traditional SS contributes significantly to the prevention of UVR-induced DNA damage and apoptosis when applied topically to human skin.

An open-label trial of L-5-hydroxytryptophan in subjects with romantic stress.

This open-label trial assessed the clinical efficacy of L-5-hydroxytryptophan (5-HTP), a natural serotonin precursor, in nondepressed young subjects with high levels of romantic stress. Since both neurotrophins and serotonin have been linked to human romantic attachment, we sought to investigate the changes in serum brain-derived neurotrophic factor (BDNF) levels and platelet serotonin content in relation to the changes in romantic stress throughout the study. A total of 15 healthy subjects (11 females and 4 males, mean age: 23.3 ± 2.1 years) who experienced a recent romantic break-up or reported recent romantic problems took part in the study. The participants were treated openly for 6 weeks with L-5-hydroxytryptophan (60 mg Griffonia simplicifolia extract containing 12.8 mg 5-HTP b.i.d., Amorex, Coropharm, Villach, Austria). The subjects were evaluated at baseline, at 3 weeks and at the end of the 6-week trial using an adapted version of the Seiffge-Krenke's Problem Questionnaire. BDNF and platelet serotonin content were determined at baseline, at 3 weeks, and after the completion of the 6-week trial. We observed significant improvements in romantic stress scores from weeks 0 through 3 (p=0.007) but no further significant improvement was evident from weeks 3 through 6 (p=0.19). At 6 weeks, subjects had a significant increase from baseline in both BDNF and platelet serotonin values. Our data suggest that direct modulation of the serotonergic system may have use for the treatment of psychological suffering associated with unreciprocated romantic love.

Serum levels of vascular endothelial growth factor and its receptors in patients with severe autism.

OBJECTIVE: To study vascular endothelial growth factor (VEGF) and its soluble receptors sVEGFR-1 and -2 in autism. DESIGN AND METHODS: We measured serum levels of angiogenic molecules in 22 patients with severe autism and 28 controls. RESULTS: Patients and controls had similar sVEGFR-2 levels, but VEGF levels were lower and sVEGFR-1 higher in patients with autism. CONCLUSION: The imbalance between VEGF and its receptor sVEGFR-1 may be involved in the pathophysiology of autism.

Serum omega-3 fatty acids are associated with ultimatum bargaining behavior.

In the ultimatum game (UG), two players are involved to bargain over a division of a given sum of money. The proposer makes an ultimatum offer of a fraction of money, while the responder can either accept or reject the proposer's decision. In case of rejection of the proposed splitting by the responder, neither player gets anything. Adverse psychological reactions are deemed to play a role in the rejection of unfair offers. Low serum levels of omega-3 polyunsaturated fatty acids have been linked to impulse control and hostility. This study examined the serum omega-3 and omega-6 fractions in relation to the ultimatum bargaining behavior. Participants were sixty economy students (31 males and 29 females, mean age: 24.4+/-2.3 years) who played a euro 10 ultimatum game. Ultimatum offers were constrained to be euro 5 (proposer keeps euro 5) or euro 1 (proposer keeps euro 9) to generate a roughly even split between fair (5:5) and unfair (1:9) offers. Fasting serum alpha-linolenic (ALA), eicosapentaenoic (EPA), docosahexaenoic acid (DHA), linoleic acid (LA) and arachidonic acid (AA) were assayed with gas chromatography. In participants who rejected unfair offers there was a significant depletion of ALA, EPA and DHA. Moreover, the ratio of serum omega-3/omega-6 fatty acids was significantly lower in patients who rejected unfair offers as compared to those who did not. The results of this study suggest that a depletion of the serum omega-3 fatty acids is associated with rejections of unfair ultimatum offers in an experimental neuroeconomic setting.

Relationship between platelet serotonin content and rejections of unfair offers in the ultimatum game.

The ultimatum game (UG), a well-studied decision task used in experimental neuroeconomics, represents a simple two-person bargaining between a proposer and a responder. The proposer offers the responder how to split a sum of money. The responder decides whether to accept or reject the offer. When the responder accepts it, each player earns money according to the proposer's offer. If the offer is rejected, neither player gets anything. Rejections of "free" money in the UG represent a deviation from the standard economic model of rationality. This behaviour could be linked to adverse psychological reactions to unfair offers, including anger, hostility and impulsiveness. Currently, it is believed that the most plausible biological system related to anger and impulsivity is the serotonergic system. We hypothesize that serotonergic activity, as measured by platelet serotonin levels, will differentiate subjects who either reject or accept low UG offers. A sample of 60 economy students (31 males and 29 females, mean age: 24.4+/-2.3 years) was investigated. As predicted, the mean platelet serotonin level was significantly lower in participants who reject unfair offers (euro 1 out of euro 10) than in those who accept (2.86+/-0.13 versus 3.48+/-0.11 nmol/10(9) platelets, respectively, p<0.001). We conclude that low platelet serotonin may serve as a reliable biomarker to identify people who are more likely to reject unfair ultimatum offers in an experimental neuroeconomic setting. Our pilot data seem to indicate that the serotonergic system may play an important role in the UG rejection behaviour.

The M694V variant of the familial Mediterranean fever gene is associated with sporadic early-onset Alzheimer's disease in an Italian population sample.

BACKGROUND: Inflammation is deemed to play a crucial role in the pathogenesis of Alzheimer's disease (AD). We sought to determine whether the proinflammatory M694V mutation of pyrin, the gene responsible for familial Mediterranean fever, could lead to an increased risk for AD. METHODS: We compared the M694V variant genotypes in 378 sporadic AD patients and 384 healthy control subjects of Italian descent. RESULTS: After adjustment for potential confounders, the M694V mutation was found to be associated with an increased risk for AD in subjects with an age at onset of 65 years or younger (multivariate-adjusted odds ratio, OR: 3.01, 95% confidence interval, CI: 1.24-6.72, p = 0.021), but not in patients with an age at onset older than 65 years (multivariate-adjusted OR: 0.81, 95% CI: 0.34-1.99, p = 0.847). Kaplan-Meier analysis indicated that AD patients bearing the M694V mutation presented with disease onset 7 years earlier than carriers of the wild-type genotype (log rank = 41.61, p < 0.001). CONCLUSION: Our data indicate that the M694V sequence variant in the pyrin gene might influence the age at onset of AD in the Italian population.

QT interval duration in apparently healthy men is associated with depression-related personality trait neuroticism.

OBJECTIVE: High levels of neuroticism and low self-esteem are markers for vulnerability to depression, a condition associated with a higher risk of arrhythmias. The question as to whether these depression-related personality domains are related to cardiac repolarization (duration of QT interval) in apparently healthy men has been addressed in this study. METHODS: Participants were 658 clinically healthy males who underwent a health screening programme. QT interval duration was determined in the resting 12-lead electrocardiogram using an automated analysis program. Neuroticism was assessed by the short-scale Eysenck Personality Questionnaire and self-esteem by the Rosenberg self-esteem scale. RESULTS: Heart-rate corrected QT interval {QTc, formula of Bazett [Bazett HC. An analysis of time relations of electrocardiograms. Heart 1920;7:353-370]} progressively increased across quartiles of neuroticism ratings. By contrast, no differences in QTc were observed across different degrees of self-esteem. A multivariate regression analysis showed that neuroticism was a statistically significant, independent predictor of QTc duration. CONCLUSION: After adjustment for potential confounders, neuroticism scores independently predicted QT interval duration in apparently healthy men. These findings highlight the possibility that higher arrhythmic risk could be present not only in patients with clinical depression but also in depression-prone, otherwise healthy individuals.

The T393C polymorphism of the GNAS1 gene is associated with deficit schizophrenia in an Italian population sample.

Programmed cell death and alterations in intracellular G-protein signaling may be involved in the pathophysiology of schizophrenia. The Galphas subunit of heterotrimeric G-proteins, encoded by the gene GNAS1, may play a role in both of these processes. Additionally, transgenic mice expressing a constitutively active form of Galphas provide a reliable model of certain endophenotypes of schizophrenia. To investigate whether the functional single nucleotide polymorphism T393C in GNAS1 gene could affect risk of schizophrenia, we examined its distribution in Italian subjects with (n=383) and without (n=400) schizophrenia. We also evaluated whether a specific association could exist between the deficit (n=108) and nondeficit (n=275) forms of the disorder. The alleles and genotypes frequency in the entire cohort of schizophrenic patients did not differ from that of controls. However, the frequency of the homozygous 393TT genotype was significantly higher in deficit schizophrenic patients (37.1%) compared to both nondeficit schizophrenic (22.5%, p=0.011) and controls (22.8%, p=0.015). This association with deficit schizophrenia persisted even after allowance for potential confounders [adjusted odds ratio (OR) for deficit schizophrenia: 2.06 (95% confidence interval (CI): 1.21-3.47), p=0.007]. Altogether, our data suggest that the GNAS1 T393C status could influence susceptibility for deficit schizophrenia in Italian subjects.

Raised plasma nerve growth factor levels associated with early-stage romantic love.

Our current knowledge of the neurobiology of romantic love remains scanty. In view of the complexity of a sentiment like love, it would not be surprising that a diversity of biochemical mechanisms could be involved in the mood changes of the initial stage of a romance. In the present study, we have examined whether the early romantic phase of a loving relationship could be associated with alterations in circulating levels of neurotrophins (NTs). Plasma levels of NGF, BDNF, NT-3 and NT-4 were measured in a total of 58 subjects who had recently fallen in love and compared with those of two control groups, consisting of subjects who were either single or were already engaged in a long-lasting relationship. NGF level was significantly higher (p < 0.001) in the subjects in love [mean (SEM): 227 (14) pg/ml] than in either the subjects with a long-lasting relationship [123 (10) pg/ml] or the subjects with no relationship [149 (12) pg/ml]. Notably, there was also a significant positive correlation between levels of NGF and the intensity of romantic love as assessed with the passionate love scale (r = 0.34; p = 0.007). No differences in the concentrations of other NTs were detected. In 39 subjects in love who-after 12-24 months-maintained the same relationship but were no longer in the same mental state to which they had referred during the initial evaluation, plasma NGF levels decreased and became indistinguishable from those of the control groups. Taken together, these findings suggest that some behavioural and/or psychological features associated with falling in love could be related to raised NGF levels in the bloodstream.