Cell-Membrane-Coated and Cell-Penetrating Peptide-Conjugated Trimagnetic Nanoparticles for Targeted Magnetic Hyperthermia of Prostate Cancer Cells.

Prostate malignancy represents the second leading cause of cancer-specific death among the male population worldwide. Herein, enhanced intracellular magnetic fluid hyperthermia is applied in vitro to treat prostate cancer (PCa) cells with minimum invasiveness and toxicity and highly specific targeting. We designed and optimized novel shape-anisotropic magnetic core-shell-shell nanoparticles (i.e., trimagnetic nanoparticles - TMNPs) with significant magnetothermal conversion following an exchange coupling effect to an external alternating magnetic field (AMF). The functional properties of the best candidate in terms of heating efficiency (i.e., Fe3O4@Mn0.5Zn0.5Fe2O4@CoFe2O4) were exploited following surface decoration with PCa cell membranes (CM) and/or LN1 cell-penetrating peptide (CPP). We demonstrated that the combination of biomimetic dual CM-CPP targeting and AMF responsiveness significantly induces caspase 9-mediated apoptosis of PCa cells. Furthermore, a downregulation of the cell cycle progression markers and a decrease of the migration rate in surviving cells were observed in response to the TMNP-assisted magnetic hyperthermia, suggesting a reduction in cancer cell aggressiveness.

Phytocannabinoids and schizophrenia: Focus on adolescence as a critical window of enhanced vulnerability and opportunity for treatment.

The recent shift in socio-political debates and growing liberalization of Cannabis use across the globe has raised concern regarding its impact on vulnerable populations such as adolescents. Concurrent with declining perception of Cannabis harms, more adolescents are using it daily in several countries and consuming marijuana strains with high content of psychotropic delta (9)-tetrahydrocannabinol (THC). These dual, related trends seem to facilitate the development of compromised social and cognitive performance at adulthood, which are described in preclinical and human studies. Cannabis exerts its effects via altering signalling within the endocannabinoid system (ECS), which modulates the stress circuitry during the neurodevelopment. In this context early interventions appear to circumvent the emergence of adult neurodevelopmental deficits. Accordingly, Cannabis sativa second-most abundant compound, cannabidiol (CBD), emerges as a potential therapeutic agent to treat neuropsychiatric disorders. We first focus on human and preclinical studies on the long-term effects induced by adolescent THC exposure as a "critical window" of enhanced neurophysiological vulnerability, which could be involved in the pathophysiology of schizophrenia and related primary psychotic disorders. Then, we focus on adolescence as a "window of opportunity" for early pharmacological treatment, as novel risk reduction strategy for neurodevelopmental disorders. Thus, we review current preclinical and clinical evidence regarding the efficacy of CBD in terms of positive, negative and cognitive symptoms treatment, safety profile, and molecular targets.

COVID-19 Disease and Vitamin D: A Mini-Review.

Novel coronavirus disease (COVID-19) pandemic caused by SARS-CoV-2, for which there is no effective treatment except employing prevention strategies, has already instituted significant number of deaths. In this review, we provide a scientific view on the potential role of vitamin D in SARS-CoV-2 virus/COVID-19 disease. Vitamin D is well-known to play a significant role in maintaining the immune health of an individual. Moreover, it induces antimicrobial peptide expression that can decrease viral replication and regulate the levels of pro-inflammatory/anti-inflammatory cytokines. Therefore, supplementation of vitamin D has the potential to reduce the incidence, severity and the risk of death from pneumonia resulting from the cytokine storm of many viral infections including COVID-19. We suggest that supplementation of subjects at high risk of COVID-19 with vitamin D (1.000 to 3.000 IU) to maintain its optimum serum concentrations may be of significant benefit for both in the prevention and treatment of the COVID-19.

Cell Membrane-Coated Magnetic Nanocubes with a Homotypic Targeting Ability Increase Intracellular Temperature due to ROS Scavenging and Act as a Versatile Theranostic System for Glioblastoma Multiforme.

In this study, hybrid nanocubes composed of magnetite (Fe3 O4 ) and manganese dioxide (MnO2 ), coated with U-251 MG cell-derived membranes (CM-NCubes) are synthesized. The CM-NCubes demonstrate a concentration-dependent oxygen generation (up to 15%), and, for the first time in the literature, an intracellular increase of temperature (6 °C) due to the exothermic scavenging reaction of hydrogen peroxide (H2 O2 ) is showed. Internalization studies demonstrate that the CM-NCubes are internalized much faster and at a higher extent by the homotypic U-251 MG cell line compared to other cerebral cell lines. The ability of the CM-NCubes to cross an in vitro model of the blood-brain barrier is also assessed. The CM-NCubes show the ability to respond to a static magnet and to accumulate in cells even under flowing conditions. Moreover, it is demonstrated that 500 µg mL-1 of sorafenib-loaded or unloaded CM-NCubes are able to induce cell death by apoptosis in U-251 MG spheroids that are used as a tumor model, after their exposure to an alternating magnetic field (AMF). Finally, it is shown that the combination of sorafenib and AMF induces a higher enzymatic activity of caspase 3 and caspase 9, probably due to an increment in reactive oxygen species by means of hyperthermia.

Effects of Vitamin D3 in Long-Term Ovariectomized Rats Subjected to Chronic Unpredictable Mild Stress: BDNF, NT-3, and NT-4 Implications.

The purpose of this study was to explore the antidepressant-like effects of vitamin D3 at different doses (1.0, 2.5, and 5.0 mg/kg sc) on a model of depression produced by chronic unpredictable mild stress (CUMS) for 28 days in long-term (3 months) ovariectomized (OVX) adult rats. Sucrose preference (SPT), forced swimming (FST) and open-field (OFT) tests were conducted to examine the depression-like state. Serum corticosterone/adrenocorticotrophic hormone (ACTH) levels and hippocampal brain-derived neurotrophic factor (BDNF) and neurotrophin (NT)-3/NT-4 expressions by ELISA kits and/or western blotting were determined to assess the possible mechanisms of the vitamin D3 effects on the depression-like profile in long-term OVX rats subjected to CUMS. The results showed that vitamin D3 (5.0 mg/kg), as well as fluoxetine treatment, considerably reversed the depression-like state in the SPT and FST, decreased serum corticosterone/ACTH levels, and increased BDNF and NT-3/NT-4 levels in the hippocampus of long-term OVX rats compared to OVX rats with CUMS (p < 0.05). Thus, a high dose of vitamin D3 (5.0 mg/kg sc) could improve the depression-like profile in long-term OVX adult female rats subjected to the CUMS procedure, which might be mediated by the regulation of BDNF and the NT-3/NT-4 signaling pathways in the hippocampus, as well as the corticosterone/ACTH levels of the blood serum.

Isolation, cultivation, and characterization of primary bovine cochlear pericytes: A new in vitro model of stria vascularis.

The study of strial pericytes has gained great interest as they are pivotal for the physiology of stria vascularis. To provide an easily accessible in vitro model, here we described a growth medium-based approach to obtain and cultivate primary bovine cochlear pericytes (BCP) from the stria vascularis of explanted bovine cochleae. We obtained high-quality pericytes in 8-10 days with a > 90% purity after the second passage. Immunocytochemical analysis showed a homogeneous population of cells expressing typical pericyte markers, such as neural/glial antigen 2 (NG2), platelet-derived growth factor receptorß (PDGFRß), α-smooth muscle actin (α-SMA), and negative for the endothelial marker von Willebrand factor. When challenged with tumor necrosis factor or lipopolysaccharide, BCP changed their shape, similarly to human retinal pericytes (HRPC). The sensitivity of BCP to ototoxic drugs was evaluated by challenging with cisplatin or gentamicin for 48 hr. Compared to human retinal endothelial cells and HRPC, cell viability of BCP was significantly lower ( p < 0.05) after the treatment with gentamicin or cisplatin. These data indicate that our protocol provides a simple and reliable method to obtain highly pure strial BCP. Furthermore, BCP are suitable to assess the safety profile of molecules which supposedly exert ototoxic activity, and may represent a valid alternative to in vivo tests.

Stimuli-responsive lipid-based magnetic nanovectors increase apoptosis in glioblastoma cells through synergic intracellular hyperthermia and chemotherapy.

In this study, taking into consideration the limitations of current treatments of glioblastoma multiforme, we fabricated a biomimetic lipid-based magnetic nanovector with a good loading capacity and a sustained release profile of the encapsulated chemotherapeutic drug, temozolomide. These nanostructures demonstrated an enhanced release after exposure to an alternating magnetic field, and a complete release of the encapsulated drug after the synergic effect of low pH (4.5), increased concentration of hydrogen peroxide (50 µM), and increased temperature due to the applied magnetic field. In addition, these nanovectors presented excellent specific absorption rate values (up to 1345 W g-1) considering the size of the magnetic component, rendering them suitable as potential hyperthermia agents. The presented nanovectors were progressively internalized in U-87 MG cells and in their acidic compartments (i.e., lysosomes and late endosomes) without affecting the viability of the cells, and their ability to cross the blood-brain barrier was preliminarily investigated using an in vitro brain endothelial cell-model. When stimulated with alternating magnetic fields (20 mT, 750 kHz), the nanovectors demonstrated their ability to induce mild hyperthermia (43 °C) and strong anticancer effects against U-87 MG cells (scarce survival of cells characterized by low proliferation rates and high apoptosis levels). The optimal anticancer effects resulted from the synergic combination of hyperthermia chronic stimulation and the controlled temozolomide release, highlighting the potential of the proposed drug-loaded lipid magnetic nanovectors for treatment of glioblastoma multiforme.

Endocannabinoid system, stress and HPA axis.

The endocannabinoid system (ECS), which is composed of the cannabinoid receptors types 1 and 2 (CB1 and CB2) for marijuana's psychoactive ingredient ∆9-tetrahydrocannabinol (∆9-THC), the endogenous ligands (AEA and 2-AG) and the enzymatic systems involved in their biosynthesis and degradation, recently emerged as important modulator of emotional and non-emotional behaviors. In addition to its recreational actions, some of the earliest reports regarding the effects of Cannabis use on humans were related to endocrine system changes. Accordingly, the ∆9-THC and later on, the ECS signalling have long been known to regulate the hypothalamic-pituitary-adrenocortical (HPA) axis, which is the major neuroendocrine stress response system of mammals. However, how the ECS could modify the stress hormone secretion is not fully understood. Thus, the present article reviews current available knowledge on the role of the ECS signalling as important mediator of interaction between HPA axis activity and stressful conditions, which, in turn could be involved in the development of psychiatric disorders.

Effects of Novel Nitric Oxide-Releasing Molecules against Oxidative Stress on Retinal Pigmented Epithelial Cells.

Oxidative stress is a hallmark of retinal degenerations such as age-related macular degeneration and diabetic retinopathy. Enhancement of heme oxygenase-1 (HO-1) activity in the retina would exert beneficial effects by protecting cells from oxidative stress, therefore promoting cell survival. Because a crosstalk exists between nitric oxide (NO) and HO-1 in promotion of cell survival under oxidative stress, we designed novel NO-releasing molecules also capable to induce HO-1. Starting from curcumin and caffeic acid phenethyl ester (CAPE), two known HO-1 inducers, the molecules were chemically modified by acylation with 4-bromo-butanoyl chloride and 2-chloro-propanoyl chloride, respectively, and then treated in the dark with AgNO3 to obtain the nitrate derivatives VP10/12 and VP10/39. Human retinal pigment epithelial cells (ARPE-19) subjected to H2O2-mediated oxidative stress were treated with the described NO-releasing compounds. VP10/39 showed significant (p < 0.05) antioxidant and protecting activity against oxidative damage, in comparison to VP10/12, which in turn showed at 100 µM concentration a slight but significant cell toxicity. Only VP10/39 significantly (p < 0.05) induced HO-1 in ARPE-19, most likely through covalent bond formation at Cys151 of the Keap1-BTB domain, as revealed from molecular docking analysis. In conclusion, the present data indicate VP10/39 as a promising candidate to protect ARPE-19 cells against oxidative stress.

Resveratrol in Hepatitis C Patients Treated with Pegylated-Interferon-α-2b and Ribavirin Reduces Sleep Disturbance.

BACKGROUND: Hepatitis C virus infection and interferon treatment have shown to be risk factors for sleep disorder health-related quality of life. AIM: To determine whether the effects of resveratrol on sleep disorders were associated with different tests in subjects with chronic hepatitis C treated with Peg-IFN-α and RBV. PATIENTS AND METHODS: In this prospective, randomized, placebo controlled, double blind clinical trial, 30 subjects (Group A) with chronic hepatitis received Pegylated-Interferon-α2b (1.5 mg/kg per week), Ribavirin and placebo (N-acetylcysteine 600 mg and lactoferrin 23.6 g), while 30 subjects (Group B) received the same dosage of Pegylated-Interferon-α2b, Ribavirin and association of N-acetylcysteine 600 mg, lactoferrin 23.6 g and Resveratrol 19.8 mg for 12 months. All subjects underwent laboratory exams and questionnaires to evaluate mood and sleep disorders (General Health Questionnaire (GHQ), Profile of Mood States (POMS), Pittsburgh Sleep Quality Inventory (PSQI), Epworth Sleepiness Scale (ESS)). RESULTS: The comparison between Group A and Group B showed significant differences after six months in C-reactive protein (p < 0.0001); after 12 months in aspartate aminotransferase (AST) (p < 0.0001) Viremia (p < 0.0001), HAI (p < 0.0012) and C-reactive protein (p < 0.0001); and at follow up in AST (p < 0.0001), Viremia (p < 0.0026) and C-reactive protein (p < 0.0001). Significant differences were observed after 12 month and follow-up in General Health Questionnaire, after 1, 6, 12 and follow-up in Profile of Mood States, after 6, 12, follow-up in Pittsburgh Sleep Quality Inventory and Epworth Sleepiness Scale. CONCLUSIONS: Supplementation with Resveratrol decreased General Health Questionnaire score and reduced sleep disorders in patients treated with Peg-IFN-α and RBV.

Endocannabinoid system in sexual motivational processes: Is it a novel therapeutic horizon?

The endocannabinoid system (ECS), which is composed of the cannabinoid receptors types 1 and 2 (CB1 and CB2) for marijuana's psychoactive ingredient Δ9-tetrahydrocannabinol (Δ9-THC), the endogenous ligands (AEA and 2-AG) and the enzymatic systems involved in their biosynthesis and degradation, recently emerged as important modulator of emotional and non-emotional behaviors. For centuries, in addition to its recreational actions, several contradictory claims regarding the effects of Cannabis use in sexual functioning and behavior (e.g. aphrodisiac vs anti-aphrodisiac) of both sexes have been accumulated. The identification of Δ9-THC and later on, the discovery of the ECS have opened a potential therapeutic target for sexual dysfunctions, given the partial efficacy of current pharmacological treatment. In agreement with the bidirectional modulation induced by cannabinoids on several behavioral responses, the endogenous cannabinoid AEA elicited biphasic effects on sexual behavior as well. The present article reviews current available knowledge on herbal, synthetic and endogenous cannabinoids with respect to the modulation of several aspects of sexuality in preclinical and human studies, highlighting their therapeutic potential.

Silybin supplementation during HCV therapy with pegylated interferon-α plus ribavirin reduces depression and anxiety and increases work ability.

BACKGROUND: Hepatitis C virus infection and interferon treatment are often associated with anxiety, depressive symptoms and poor health-related quality of life. To evaluate the Silybin-vitamin E-phospholipids complex effect on work ability and whether health related factors (anxiety and depression) were associated with work ability in subjects with chronic hepatitis C treated with Pegylated-Interferon-α2b (Peg-IFN) and Ribavirin (RBV). METHODS: Thirty-one patients (Group A) with chronic hepatitis and other 31 subjects in Group B were recruited in a randomized, prospective, placebo controlled, double blind clinical trial. Group A received 1.5 mg/kg per week of Peg-IFN plus RBV and placebo, while Group B received the same dosage of Peg-IFN plus RBV plus association of Silybin 94 mg + vitamin E 30 mg + phospholipids 194 mg in pills for 12 months. All subjects underwent to laboratory exams and questionnaires to evaluate depression (Beck Depression Inventory - BDI), anxiety (State-trait anxiety inventory - STAI) and work ability (Work ability Index - WAI). RESULTS: The comparison between group A and group B showed significant differences after 6 months in ALT (P < 0.001), and viremia (P < 0.05), after 12 months in ALT (P < 0.001), and AST (P < 0.001), at follow up in AST (P < 0.05), and ALT (P < 0.001). Significant difference were observed after 1 month in WAI (p < 0.001) and BDI (P < 0.05), after 6 months in WAI (P < 0.05) and STAI (P < 0.05), after 12 months and at follow up in WAI, STAI and BDI (p < 0.01). CONCLUSIONS: The supplementation with Silybin-vitamin E -phospholipids complex increased work ability and reduced depression and anxiety in patients treated with Peg-IFN and RBV. TRIAL REGISTRATION: NCT01957319 , First received: September 25, 2013. Last updated: September 30, 2013 (retrospectively registered).

Nrf2 activators modulate oxidative stress responses and bioenergetic profiles of human retinal epithelial cells cultured in normal or high glucose conditions.

Retinal pigment epithelial cells exert an important supporting role in the eye and develop adaptive responses to oxidative stress or high glucose levels, as observed during diabetes. Endogenous antioxidant defences are mainly regulated by Nrf2, a transcription factor that is activated by naturally-derived and electrophilic compounds. Here we investigated the effect of the Nrf2 activators dimethylfumarate (DMF) and carnosol on antioxidant pathways, oxygen consumption rate and wound healing in human retinal pigment epithelial cells (ARPE-19) cultured in medium containing normal (NG, 5mM) or high (HG, 25 mM) glucose levels. We also assessed wound healing using an in vivo corneal epithelial injury model. We found that Nrf2 nuclear translocation and heme oxygenase activity increased in ARPE cells treated with 10 µM DMF or carnosol irrespective of glucose culture conditions. However, HG rendered retinal cells more sensitive to regulators of glutathione synthesis or inhibition and caused a decrease of both cellular and mitochondrial reactive oxygen species. Culture in HG also reduced ATP production and mitochondrial function as measured with the Seahorse XF analyzer and electron microscopy analysis revealed morphologically damaged mitochondria. Acute treatment with DMF or carnosol did not restore mitochondrial function in HG cells; conversely, the compounds reduced cellular maximal respiratory and reserve capacity, which were completely prevented by N-acetylcysteine thus suggesting the involvement of thiols in this effect. Interestingly, the scratch assay showed that wound closure was faster in cells cultured in HG than NG and was accelerated by carnosol. This effect was reversed by an inhibitor of heme oxygenase activity. Moreover, topical application of carnosol to the cornea of diabetic rats significantly accelerated wound healing. In summary, these data indicate that culture of retinal epithelial cells in HG does not affect the activation of the Nrf2/heme oxygenase axis but influences other crucial oxidative and mitochondrial-dependent cellular functions. The additional effect on wound closure suggests that results obtained in in vitro experimental settings need to be carefully evaluated in the context of the glucose concentrations used in cell culture.

Silybin-vitamin E-phospholipids complex reduces liver fibrosis in patients with chronic hepatitis C treated with pegylated interferon α and ribavirin.

Chronic hepatitis C is both a virologic and a fibrotic disease, with mortality resulting mainly from the complications of cirrhosis and HCC. The aim was to evaluate the impact on of supplementation with a new pharmaceutical complex of silybinvitamin E-phospholipids in patients with chronic hepatitis C treated with Pegylated-Interferon-α2b plus Ribavirin. In this prospective, randomized, placebo controlled, double blind clinical trial, 32 subjects with chronic hepatitis, received Pegylated-Interferon-α2b (1.5 mg/kg per week) plus Ribavirin and placebo, while 32 subjects received the same dosage of Pegylated-Interferon-α2b plus Ribavirin plus association of Silybin 47 mg + vitamin E 15 mg + phospholipids 97 mg in two pill for 12 months. Serum levels of the following markers of liver fibrosis were evaluated: transforming growth factor beta, hyaluronic acid, metalloproteinase 2, amino-terminal pro-peptide of type III procollagen, tissue inhibitor of matrix metalloproteinase type I. The comparison between group A and group B showed a significant difference in ALT (P<0.001), and viremia (P<0.05) after 12 months; in TGF beta levels after 12 months and at follow up (P<0.05); in MMP-2 after 6 months (P<0.05); in PIIINP after 6, 12 months and at follow up (P<0.05); in TIMP-1 after 6, 12 months and at follow up (P<0.001). In conclusion, the supplementation with silybin-vitamin E-phosholipids complex ameliorated the response to Peg-IFN plus RBV treatment and reduced serum levels of markers of liver fibrosis. The ameliorative effect of the complex maybe related to a direct effect on the activation of hepatic stellate cells, or mediated via antioxidants.

Acetyl-L-Carnitine Supplementation During HCV Therapy With Pegylated Interferon-α 2b Plus Ribavirin: Effect on Work Performance; A Randomized Clinical Trial.

BACKGROUND: The health status of employees with chronic hepatitis C has major implications for organizations and labour market. OBJECTIVES: To assess the effects of Acetyl-L-Carnitine administration on work productivity, daily activity, and fatigue in subjects with chronic hepatitis C treated with Pegylated-Interferon-α2b and Ribavirin. PATIENTS AND METHODS: In this prospective, randomized, placebo controlled, double blind clinical trial, 30 subjects (Group A) with chronic hepatitis, received Pegylated-Interferon-α2b (1.5 mg/kg per week) plus Ribavirin and placebo, while 32 subjects (Group B) received the same dosage of Pegylated-Interferon-α2b plus Ribavirin plus 2g Acetyl-L-Carnitine twice per day, for 12 months. Work productivity loss, impairment in daily activities, presenteeism, absenteeism, have been assessed using the Work Productivity and Activity Impairment questionnaire. We also evaluated severity of fatigue, mental fatigue and physical fatigue. RESULTS: Significant difference were observed in physical fatigue, mental fatigue and severity of fatigue, aspartate aminotransferase, alanine aminotransferase, and viremia after 12 months treatment. In Group B we observed a significant decrease of presenteeism and daily activity impairment after 6 months, 12 months and at follow up. A significant increase of work productivity was observed after 12 months and at follow up. CONCLUSIONS: Office workers with chronic hepatitis C, treated with Pegylated-Interferon-α2b plus Ribavirin, had work performance loss. In subjects treated with Acetyl-L-Carnitine supplementation we observed increased daily activity and reduced presenteeism and fatigue. Acetyl-L-Carnitinegroup had a smaller reduction of productivity comparing to placebo group.

Role of omega-3 fatty acids in the treatment of depressive disorders: a comprehensive meta-analysis of randomized clinical trials.

BACKGROUND: Despite omega-3 polyunsaturated fatty acids (PUFA) supplementation in depressed patients have been suggested to improve depressive symptomatology, previous findings are not univocal. OBJECTIVES: To conduct an updated meta-analysis of randomized controlled trials (RCTs) of omega-3 PUFA treatment of depressive disorders, taking into account the clinical differences among patients included in the studies. METHODS: A search on MEDLINE, EMBASE, PsycInfo, and the Cochrane Database of RCTs using omega-3 PUFA on patients with depressive symptoms published up to August 2013 was performed. Standardized mean difference in clinical measure of depression severity was primary outcome. Type of omega-3 used (particularly eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) and omega-3 as mono- or adjuvant therapy was also examined. Meta-regression analyses assessed the effects of study size, baseline depression severity, trial duration, dose of omega-3, and age of patients. RESULTS: Meta-analysis of 11 and 8 trials conducted respectively on patients with a DSM-defined diagnosis of major depressive disorder (MDD) and patients with depressive symptomatology but no diagnosis of MDD demonstrated significant clinical benefit of omega-3 PUFA treatment compared to placebo (standardized difference in random-effects model 0.56 SD [95% CI: 0.20, 0.92] and 0.22 SD [95% CI: 0.01, 0.43], respectively; pooled analysis was 0.38 SD [95% CI: 0.18, 0.59]). Use of mainly EPA within the preparation, rather than DHA, influenced final clinical efficacy. Significant clinical efficacy had the use of omega-3 PUFA as adjuvant rather than mono-therapy. No relation between efficacy and study size, baseline depression severity, trial duration, age of patients, and study quality was found. Omega-3 PUFA resulted effective in RCTs on patients with bipolar disorder, whereas no evidence was found for those exploring their efficacy on depressive symptoms in young populations, perinatal depression, primary disease other than depression and healthy subjects. CONCLUSIONS: The use of omega-3 PUFA is effective in patients with diagnosis of MDD and on depressive patients without diagnosis of MDD.

Omega-3 fatty acids and depression: scientific evidence and biological mechanisms.

The changing of omega-6/omega-3 polyunsaturated fatty acids (PUFA) in the food supply of Western societies occurred over the last 150 years is thought to promote the pathogenesis of many inflammatory-related diseases, including depressive disorders. Several epidemiological studies reported a significant inverse correlation between intake of oily fish and depression or bipolar disorders. Studies conducted specifically on the association between omega-3 intake and depression reported contrasting results, suggesting that the preventive role of omega-3 PUFA may depend also on other factors, such as overall diet quality and the social environment. Accordingly, tertiary prevention with omega-3 PUFA supplement in depressed patients has reached greater effectiveness during the last recent years, although definitive statements on their use in depression therapy cannot be yet freely asserted. Among the biological properties of omega-3 PUFA, their anti-inflammatory effects and their important role on the structural changing of the brain should be taken into account to better understand the possible pathway through which they can be effective both in preventing or treating depression. However, the problem of how to correct the inadequate supply of omega-3 PUFA in the Westernized countries' diet is a priority in order to set food and health policies and also dietary recommendations for individuals and population groups.

Therapeutic potential of cannabinoids in schizophrenia.

Increasing evidence suggests a close relationship between the endocannabinoid system and schizophrenia. The endocannabinoid system comprises of two G protein-coupled receptors (the cannabinoid receptors 1 and 2 [CB1 and CB2] for marijuana's psychoactive principle Δ(9)-tetrahydrocannabinol), their endogenous small lipid ligands (namely anandamide [AEA] and 2-arachidonoylglycerol [2-AG], also known as endocannabinoids), and proteins for endocannabinoid biosynthesis and degradation. It has been suggested to be a pro-homeostatic and pleiotropic signalling system activated in a time- and tissue-specific manner during pathophysiological conditions. In the brain, activation of this system impacts the release of numerous neurotransmitters in various systems and cytokines from glial cells. Hence, the endocannabinoid system is strongly involved in neuropsychiatric disorders, such as schizophrenia. Therefore, adolescence use of Cannabis may alter the endocannabinoid signalling and pose a potential environmental risk to develop psychosis. Consistently, preclinical and clinical studies have found a dysregulation in the endocannabinoid system such as changed expression of CB1 and CB2 receptors or altered levels of AEA and 2-AG . Thus, due to the partial efficacy of actual antipsychotics, compounds which modulate this system may provide a novel therapeutic target for the treatment of schizophrenia. The present article reviews current available knowledge on herbal, synthetic and endogenous cannabinoids with respect to the modulation of schizophrenic symptomatology. Furthermore, this review will be highlighting the therapeutic potential of cannabinoid-related compounds and presenting some promising patents targeting potential treatment options for schizophrenia.

Pharmacological and dietary prevention for colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer morbidity and mortality. People at higher risk are those individuals with a family history of CRC and familial adenomatous polyposis. Prevention and screening are two milestones for this disease. The aim of this study is to evaluate the chemopreventive role of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin and cyclooxygenase 2 inhibitors, some micronutrients (folic acid, calcium, selenium, antioxidants) and probiotics. DISCUSSION: The studies on aspiring reported promising results, but it is debatable whether aspirin should be used as chemoprevention, because of its side effects and because of poor efficacy evident in subjects at high risk. Similar results were reported for other non-aspirin NSAIDs, such as sulindac and celecoxib, which the potential adverse effects limit their use. Selenium role in prevention of various types of cancer as well as in colon adenomas are often inconclusive or controversial. Several studies suggested that calcium may have a possible chemopreventive effect on colon adenomas and CRC, although contrasting results are reported for the latter. A recent meta-analysis including 13 randomized trial suggested that folic acid supplementation had not a chemiopreventive action on CRC. Several studies investigated the association between antioxidants, administered alone or in combination, and CRC risk, both among general and at risk population, but only few of them supported statistically significant results. CONCLUSION: The results of this literature review showed an unclear role in CRC prevention of both pharmacological and dietary intervention. Despite several options are available to prevent colon cancer, it is challenging to identify a correct strategy to prevent CRC through pharmacological and dietary intervention due to the long latency of cancer promotion and development. Since some of the drugs investigated may have uncertain individual effects, it can be suggested to potentiate such effects by adding them together.

Red orange: experimental models and epidemiological evidence of its benefits on human health.

In recent years, there has been increasing public interest in plant antioxidants, thanks to the potential anticarcinogenic and cardioprotective actions mediated by their biochemical properties. The red (or blood) orange (Citrus sinensis (L.) Osbeck) is a pigmented sweet orange variety typical of eastern Sicily (southern Italy), California, and Spain. In this paper, we discuss the main health-related properties of the red orange that include anticancer, anti-inflammatory, and cardiovascular protection activities. Moreover, the effects on health of its main constituents (namely, flavonoids, carotenoids, ascorbic acid, hydroxycinnamic acids, and anthocyanins) are described. The red orange juice demonstrates an important antioxidant activity by modulating many antioxidant enzyme systems that efficiently counteract the oxidative damage which may play an important role in the etiology of numerous diseases, such as atherosclerosis, diabetes, and cancer. The beneficial effects of this fruit may be mediated by the synergic effects of its compounds. Thus, the supply of natural antioxidant compounds through a balanced diet rich in red oranges might provide protection against oxidative damage under differing conditions and could be more effective than, the supplementation of an individual antioxidant.