ECHOPvir: A Mixture of Echinacea and Hop Extracts Endowed with Cytoprotective, Immunomodulatory and Antiviral Properties.

Respiratory viral infections continue to pose significant challenges, particularly for more susceptible and immunocompromised individuals. Nutraceutical strategies have been proposed as promising strategies to mitigate their impact and improve public health. In the present study, we developed a mixture of two hydroalcoholic extracts from the aerial parts of Echinacea purpurea (L.) Moench (ECP) and the cones of Humulus lupulus L. (HOP) that can be harnessed in the prevention and treatment of viral respiratory diseases. The ECP/HOP mixture (named ECHOPvir) was characterized for the antioxidant and cytoprotective properties in airway cells. Moreover, the immunomodulating properties of the mixture in murine macrophages against antioxidant and inflammatory stimuli and its antiviral efficacy against the PR8/H1N1 influenza virus were assayed. The modulation of the Nrf2 was also investigated as a mechanistic hypothesis. The ECP/HOP mixture showed a promising multitarget bioactivity profile, with combined cytoprotective, antioxidant, immunomodulating and antiviral activities, likely due to the peculiar phytocomplexes of both ECP and HOP, and often potentiated the effect of the single extracts. The Nrf2 activation seemed to trigger these cytoprotective properties and suggest a possible usefulness in counteracting the damage caused by different stressors, including viral infection. Further studies may strengthen the interest in this product and underpin its future nutraceutical applications.

Interaction of Garcinia cambogia (Gaertn.) Desr. and Drugs as a Possible Mechanism of Liver Injury: The Case of Montelukast.

Overweight and obesity prevalence has increased worldwide. Apart from conventional approaches, people also resort to botanical supplements for reducing body weight, although several adverse events have been associated with these products. In this context, the present study aimed at evaluating the toxicity of Garcinia cambogia-based products and shedding light on the mechanisms involved. The suspected hepatotoxic reactions related to G. cambogia-containing products collected within the Italian Phytovigilance System (IPS) were examined. Then, an in vitro study was performed to evaluate the possible mechanisms responsible for the liver toxicity, focusing on the modulation of oxidative stress and Nrf2 expression. From March 2002 to March 2022, the IPS collected eight reports of hepatic adverse reactions related to G. cambogia, which exclusively involved women and were mostly severe. The causality assessment was probable in three cases, while it was possible in five. In the in vitro experiments, a low cytotoxicity of G. cambogia was observed. However, its combination with montelukast greatly reduced cell viability, increased the intracellular ROS levels, and affected the cytoplasmic Nrf2 expression, thus suggesting an impairment of the antioxidant and cytoprotective defenses. Overall, our results support the safety concerns about G. cambogia-containing supplements and shed light on the possible mechanisms underpinning its hepatotoxicity.

Recent Advances in the Neuroprotective Properties of Ferulic Acid in Alzheimer's Disease: A Narrative Review.

Alzheimer's disease (AD) is a progressive degenerative disorder of the central nervous system, characterized by neuroinflammation, neurotransmitter deficits, and neurodegeneration, which finally leads to neuronal death. Emerging evidence highlighted that hyperglycemia and brain insulin resistance represent risk factors for AD development, thus suggesting the existence of an additional AD form, associated with glucose metabolism impairment, named type 3 diabetes. Owing to the limited pharmacological options, novel strategies, especially dietary approaches based on the consumption of polyphenols, have been addressed to prevent or, at least, slow down AD progression. Among polyphenols, ferulic acid is a hydroxycinnamic acid derivative, widely distributed in nature, especially in cereal bran and fruits, and known to be endowed with many bioactivities, especially antioxidant, anti-inflammatory and antidiabetic, thus suggesting it could be exploited as a possible novel neuroprotective strategy. Considering the importance of ferulic acid as a bioactive molecule and its widespread distribution in foods and medicinal plants, the aim of the present narrative review is to provide an overview on the existing preclinical and clinical evidence about the neuroprotective properties and mechanisms of action of ferulic acid, also focusing on its ability to modulate glucose homeostasis, in order to support a further therapeutic interest for AD and type 3 diabetes.

Efficacy and Safety of Oral Green Tea Preparations in Skin Ailments: A Systematic Review of Clinical Studies.

Green-tea-based products and their polyphenols, especially epigallocatechin-3-gallate, have attracted great attention over the years as possible nutraceuticals, due to their promising bioactivities, especially antioxidant and anti-inflammatory, which could be exploited in several diseases, including skin ailments. In this context, the present study aimed at reviewing clinical evidence about the benefits of the oral administration of green tea preparations and its polyphenols to relieve skin disorders, to point out the current knowledge, and to suggest possible novel strategies to effectively exploit the properties of green tea, also managing safety risks. To this end, a systematic review of the existing literature was carried out, using the PRISMA method. Few studies, including five focused on UV-induced erythema and skin alterations, three on photoaging, two on antioxidant skin defenses, and one on acne and genodermatosis, were retrieved. Despite several benefits, clinical evidence only supports the use of oral green tea preparations to protect skin from damage induced by ultraviolet radiation; in other cases, conflicting results and methodological limits of clinical trials do not allow one to clarify their efficacy. Therefore, their application as adjuvant or alternative sunscreen-protective interventions could be encouraged, in compliance with the safety recommendations.

Adverse events related to herbal dietary supplements and over-the-counter medications containing laxatives: a 10-year update from the Italian Phytovigilance and Pharmacovigilance systems.

INTRODUCTION: Products containing anthraquinones (AQ) are associated with an increased risk of serious adverse events (AEs). We performed an update of the available evidence retrieved by the spontaneous reports of AE associated with herbal dietary supplement (DS) and over-the-counter medications (OTC-M) used as laxatives. METHODS: Analysis and evaluation of AE reports retrieved from the Italian Phytovigilance and Pharmacovigilance systems was performed from February 2011 to December 2020. RESULTS: Totally 110 AE reports, 24 related to herbal DS and 86 to OTC-M, were analyzed. Most subjects were females. Herbal products analyzed mostly contained AQ derivatives. Most AEs were gastrointestinal (41.6%), central nervous system (18.2%), and dermatological disorders (12.6%). CONCLUSIONS: The number of AE reports recorded in the last 10 years is still relatively low. However, given the seriousness of some AEs, that does not represent a guarantee of safety. This study may contribute to enhance public awareness on the risks associated with misuse or abuse of laxatives.

Characterization of the Phytochemical Composition and Bioactivities of Anacyclus maroccanus Ball. and Anacyclus radiatus Loisel Aerial Parts: Preliminary Evidence for the Possible Development of Moroccan Plants.

In the present study, the phytochemical composition and bioactivities of A. maroccanus (AM) and A. radiatus (AR), two ecotypes collected in the Demnate road and Essaouira regions, respectively, were studied to highlight a pharmacological interest and to enable possible pharmaceutical development. To this end, methanolic and ethyl acetate extracts were prepared for each ecotype by fractionation; next, their phytochemical composition was evaluated by spectrophotometric and chromatographic analysis. Moreover, in line with the available evidence for Anacyclus spp. and their traditional use, a screening of bioactivities, including antioxidant, hypoglycemic, antiglycative, chelating, and antibacterial activities, was performed. The extracts were characterized by high amounts of polyphenols, tannins, and flavonoids, especially in the methanolic extracts; these samples were also enriched in carotenoids despite a lower chlorophyll content. Chlorogenic acid and rutin were the major identified compounds. The extracts also showed interesting hypoglycemic, antiglycative, and antibacterial properties, although with differences in efficacy and potency. Present results provide more scientific basis to the ethnopharmacological uses of Anacyclus spp. and suggest a further interest in AM and AR ecotypes as natural sources of bioactive compounds and/or phytocomplexes for possible pharmaceutical and nutraceutical developments.

Anthraquinone laxatives use and colorectal cancer: A systematic review and meta-analysis of observational studies.

This systematic review and meta-analysis were conducted to determine the effects of anthraquinone (AQ) laxatives on colorectal cancer (CRC). We searched PubMed, Embase, Google Scholar, and CENTRAL from inception until March 2021, for randomized controlled trials (RCTs) and observational studies. Through the systematic review, we identified 8 observational studies evaluating AQ laxatives use as a risk factor for CRC development, and 5 studies on CRC risk were included in the meta-analysis using a random-effects model. Through the meta-analysis, we found that a history of AQ laxatives use compared with "other" and "no laxatives" use was associated with CRC development (OR: 1.41; 95% CI: 0.94-2.11), although not at a statistically significant level. The possible association persists even after removal of the outlier studies (OR: 1.51; 95% CI: 0.97-2.34). Selection of cases and controls was judged at low or unclear risk of bias across almost all studies, and the quality of evidence was from moderate to low. In conclusion, it is not possible to associate the use of AQ laxatives with the development of CRC. However, the trend toward an increased risk of CRC provides a strong indication for investigating this issue by performing further high-quality studies.

Suspected adverse reactions to performance enhancing dietary supplements: Spontaneous reports from the Italian phytovigilance system.

Herbal tonic and adaptogens are often used to improve overall well-being. However, few clinical evidence supports their use and their safety is not known before marketing. In this context, the aim of our study was to analyze the spontaneous reports of suspected adverse reactions (ARs) to performance enhancing herbal dietary supplements collected by the Italian Phytovigilance System. Between March 2002 and September 2020, 110 spontaneous reports were collected, 58 of which related to products containing botanicals, alone or in association. Twenty-three serious reactions were reported, 21 of which required hospitalization, one was life-threatening and another caused disability. Dermatological and cardiovascular reactions were the most frequent. Hepatic ARs were the most serious (9 out of 10). A positive dechallenge was indicated in 69% of cases, while a positive rechallenge occurred in 15%. Concomitant use of other products was present in 18 reports (31%), while predisposing conditions were indicated in 17 (29%). Present data highlight safety concerns on herbal dietary supplements used as cognitive and physical performance enhancers, mainly due to their quality and use without expert supervision. Considering that postmarketing surveillance is not required for these products, spontaneous reports represent the only tool to point out risks related to food supplements.

Assessment of adverse reactions to α-lipoic acid containing dietary supplements through spontaneous reporting systems.

BACKGROUND & AIMS: Alpha-lipoic acid (ALA)-containing dietary supplements are widely used in clinical practice, although their safety assessment is under-investigated. We characterize the safety profile of ALA-containing products by analysing spontaneous reports of suspected adverse reactions (ARs). METHODS: Suspected ARs to ALA-containing products were extracted from the Italian Phytovigilance System (IPS), and scrutinized in terms of seriousness and causality (through WHO UMC system), with a specific focus on important (IMEs) and designated medical events (DMEs). To characterize the reporting profile from an international perspective, the WHO-VigiBase was also queried. RESULTS: From March 2002 to February 2020, out of 2147 total reports, 116 reports concerning 212 ARs to ALA-containing products were collected. Women were involved in 68.1% of cases. Skin (44.9%) and gastrointestinal disorders (10.8%) were the most frequently represented ARs. Causality assessment resulted as definite (15), probable (35), possible (24), unlikely (5), and unclassifiable (37). In 70% of cases, events occurred within 30 days of ALA use. Forty-five reports were serious (38.8%), being insulin autoimmune syndrome the most frequently reported (N = 10). IMEs were recorded in 20 cases, including four DMEs (3 angioedema and one anaphylactic shock). Similar distribution emerged from the 5641 reports in the WHO-VigiBase. CONCLUSIONS: The remarkable reporting of unpredictable skin, immune and hepatic ARs, coupled with seriousness, strong causality and early onset, calls for a) careful risk-benefit assessment of ALA-containing products by regulators; b) awareness and monitoring by clinicians and c) continuous vigilance of their safety profile through valuable spontaneous reporting systems such as IPS.

Turmeric (Curcuma longa L.) food supplements and hepatotoxicity: an integrated evaluation approach.

INTRODUCTION: Turmeric is the common name for the rhizome of Curcuma longa L. In the recent years, food supplements containing turmeric have been marketed and widely used by an increasing number of consumers. Spontaneous reports of suspected adverse reactions to food supplements are collected within the Phytovigilance system. METHODS: An ad hoc multidisciplinary group investigated the suspected cases of hepatotoxicity reported to the Italian Phytovigilance system associated with the assumption of turmeric food supplements with the methodology specific to pharmacovigilance as well as for the evaluation of the quality and safety of food supplements. RESULTS: A cluster of 28 spontaneous reports of acute hepatitis, mostly with cholestasis, associated with turmeric products were sent to the Italian Phytovigilance system in the first six months of 2019. In all cases, except one, the causality assessment was at least possible. The suspected products were collected and analysed for the presence of drugs, heavy metals, aflatoxins, pesticides, synthetic dyes and pyrrolizidine alkaloids. CONCLUSION: On the basis of the results of all the activities performed by multidisciplinary group, regulatory intervention was taken. This study highlights the importance of developing an integrated evaluation approach for the evaluation of the adverse effects associated with the use of food supplements.

Modulation of STAT3 Signaling, Cell Redox Defenses and Cell Cycle Checkpoints by ß-Caryophyllene in Cholangiocarcinoma Cells: Possible Mechanisms Accounting for Doxorubicin Chemosensitization and Chemoprevention.

Cholangiocarcinoma (CCA) is an aggressive group of biliary tract cancers, characterized by late diagnosis, low effective chemotherapies, multidrug resistance, and poor outcomes. In the attempt to identify new therapeutic strategies for CCA, we studied the antiproliferative activity of a combination between doxorubicin and the natural sesquiterpene ß-caryophyllene in cholangiocarcinoma Mz-ChA-1 cells and nonmalignant H69 cholangiocytes, under both long-term and metronomic schedules. The modulation of STAT3 signaling, oxidative stress, DNA damage response, cell cycle progression and apoptosis was investigated as possible mechanisms of action. ß-caryophyllene was able to synergize the cytotoxicity of low dose doxorubicin in Mz-ChA-1 cells, while producing cytoprotective effects in H69 cholangiocytes, mainly after a long-term exposure of 24 h. The mechanistic analysis highlighted that the sesquiterpene induced a cell cycle arrest in G2/M phase along with the doxorubicin-induced accumulation in S phase, reduced the γH2AX and GSH levels without affecting GSSG. ROS amount was partly lowered by the combination in Mz-ChA-1 cells, while increased in H69 cells. A lowered expression of doxorubicin-induced STAT3 activation was found in the presence of ß-caryophyllene in both cancer and normal cholangiocytes. These networking effects resulted in an increased apoptosis rate in Mz-ChA-1 cells, despite a lowering in H69 cholangiocytes. This evidence highlighted a possible role of STAT3 as a final effector of a complex network regulated by ß-caryophyllene, which leads to an enhanced doxorubicin-sensitivity of cholangiocarcinoma cells and a lowered chemotherapy toxicity in nonmalignant cholangiocytes, thus strengthening the interest for this natural sesquiterpene as a dual-acting chemosensitizing and chemopreventive agent.

Hypoglycemic, Antiglycation, and Cytoprotective Properties of a Phenol-Rich Extract From Waste Peel of Punica granatum L. var. Dente di Cavallo DC2.

Pomegranate peel is a natural source of phenolics, claimed to possess healing properties, among which are antioxidant and antidiabetic. In the present study, an ethyl acetate extract, obtained by Soxhlet from the peel of Dente di Cavallo DC2 pomegranate (PGE) and characterized to contain 4% w/w of ellagic acid, has been evaluated for its hypoglycemic, antiglycation, and antioxidative cytoprotective properties, in order to provide possible evidence for future nutraceutical applications. The α-amylase and α-glucosidase enzyme inhibition, interference with advanced glycation end-products (AGE) formation, and metal chelating abilities were studied. Moreover, the possible antioxidant cytoprotective properties of PGE under hyperglycemic conditions were assayed. Phenolic profile of the extract was characterized by integrated chromatographic and spectrophotometric methods. PGE resulted able to strongly inhibit the tested enzymes, especially α-glucosidase, and exerted chelating and antiglycation properties. Also, it counteracted the intracellular oxidative stress under hyperglycemic conditions, by reducing the levels of reactive oxygen species and total glutathione. Among the identified phenolics, rutin was the most abundant flavonoid (about 4 % w/w). Present results suggest PGE to be a possible remedy for hyperglycemia management and encourage further studies to exploit its promising properties.

Suspected adverse reactions associated with herbal products used for weight loss: spontaneous reports from the Italian Phytovigilance System.

PURPOSE: Overweight and obesity represent worldwide a rising health problem. In this context, dietary supplements and herbal preparations are often used as self-medication for weight loss. The aim of this study was to describe the safety profile of dietary supplements for weight control by analyzing spontaneous reports of suspected adverse reactions (ARs) received by the Italian Phytovigilance System, from July 2010 to October 2017. METHODS: The suspected ARs were collected using an ad hoc reporting form, registered in a database at the National Institute of Health and evaluated by a multidisciplinary group of experts. The causality assessment was performed using the WHO-UMC system or the CIOMS/RUCAM score. In case of serious adverse reactions, a feedback is provided to the reporter by e-mail. RESULTS: Sixty-six spontaneous reports were collected. ARs involved cardiovascular system (26%), liver (14%), central nervous system (12%), skin (9%), gastrointestinal system (17%), thyroid (8%), kidney (4%), and other organs/systems (10%). In 64% of cases, the reaction was serious. Dechallenge was positive in 46 cases; three cases of positive rechallenge were reported. After the causality assessment, the association between the product intake and the adverse reaction was judged as possible in the majority of the cases (n = 43; 65%). CONCLUSIONS: The data collected confirmed the existence of safety concerns on herbal dietary supplements used for body weight control, mainly related to quality of products and their use as self-medication. In this scenario, spontaneous reports represent the only tools available to monitor safety of these products.

Adverse Events to Food Supplements Containing Red Yeast Rice: Comparative Analysis of FAERS and CAERS Reporting Systems.

INTRODUCTION: Food supplements containing red yeast rice (RYR) are proposed as an alternative in statin-intolerant patients, although they actually contain natural statin(s) and their safety in clinical practice is still incompletely characterized. We described and compared adverse events (AEs) associated with RYR products submitted to reporting systems maintained by the Food and Drug Administration (FDA), with a focus on liver and muscular events. METHODS: We extracted RYR-related AEs from the FDA Adverse Event Reporting System (FAERS) [first quarter (Q1)-2004 to Q2-2016], a drug-based archive, and the Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS) (Q1-2004 to Q1-2017). Disproportionality via reporting odds ratio (ROR) with 95% confidence interval (CI) calculation and case-by-case inspection were performed, with a focus on muscular and hepatic AEs. RESULTS: One thousand three hundred AEs were extracted from FAERS (RYR mainly reported as a concomitant agent), whereas only 159 AEs were found in CAERS (RYR recorded mainly as a suspect agent). In FAERS, a large number of reports emerged for "general disorders and administration site conditions," whereas CAERS received also a high number of reports for "investigations" and "musculoskeletal and connective tissue disorders". Disproportionality analyses confirmed higher reporting of serious muscular and liver injuries: in FAERS, five cases of hepatic disorders (ROR = 13.71; 95% CI 5.44-34.57); in CAERS, 27 cases of rhabdomyolysis/myopathy (8.44; 5.44-13.10). CONCLUSIONS: Notwithstanding recognized limitations, these findings strengthen the importance of exploring multiple databases in safety assessment of RYR products, which should be monitored by clinicians for muscular and hepatic safety, and call for urgent review by policymakers to harmonize their regulatory status.

Phytochemical analysis and effects on ingestive behaviour of a Caralluma fimbriata extract.

Caralluma fimbriata Wall. is currently used as a "natural slimming" food supplement, likely due to its content in pregnane glycosides. In the present study, a commercially available Caralluma fimbriata extract (Slimaluma®; CFE, 100 mg/kg) has been evaluated for its ability to affect the ingestive behaviour in female rats, also with reference to the modulation of the brain neuropeptides NPY and ORX.The interference of CFE with α-amylase and lipase enzymes has been investigated in vitro, as possible peripheral mechanism of action. Also, the chemical composition of CFE has been assessed by NMR and spectrophotometric analysis. Results from in vivo study showed that CFE induced effects neither on blood parameters, nor on liver and gut histomorphology. Interestingly, a reduction in body weight gain with an increase in water intake and hypothalamic levels of NPY and ORX peptides were found. Phytochemical analysis, showed CFE contained about 12% of pregnane glycosides and 1.3% of polyphenols. Present results suggest possible effects of C. fimbriata on ingestive behaviour, likely mediated by central and peripheral mechanisms.

Genotoxicity assessment of piperitenone oxide: An in vitro and in silico evaluation.

Piperitenone oxide, a natural flavouring agent also known as rotundifolone, has been studied for the genotoxicity assessment by an integrated in vitro and in silico experimental approach, including the bacterial reverse mutation assay, the micronucleus test, the comet assay and the computational prediction by Toxtree and VEGA tools. Under our experimental conditions, the monoterpene showed to induce both point mutations (i.e. frameshift, base-substitution and/or oxidative damage) and DNA damage (i.e. clastogenic or aneuploidic damage, or single-strand breaks). Computational prediction for piperitenone oxide agreed with the toxicological data, and highlighted the presence of the epoxide function and the α,ß-unsaturated carbonyl as possible structural alerts for DNA damage. However, improving the toxicological libraries for natural occurring compounds is required in order to favour the applicability of in silico models to the toxicological predictions. Further in vivo evaluations are strictly needed in order to evaluate the role of the bioavailability of the substance and the metabolic fate on its genotoxicity profile. To the best of our knowledge, these data represent the first evaluation of the genotoxicity for this flavour compound and suggest the need of further studies to assess the safety of piperitenone oxide as a flavouring agent.

Adverse reactions to dietary supplements containing red yeast rice: assessment of cases from the Italian surveillance system.

AIMS: Red yeast rice (RYR) is contained in dietary supplements for patients with dyslipidemia. RYR supplements contain monacolin K, which is chemically identical to lovastatin, a licensed drug with a well-known risk profile. We aim to describe the safety profile of RYR by analysing spontaneous reports of suspected adverse reactions (ARs). METHODS: Within the Italian Surveillance System of Natural Health Products, suspected ARs were collected and evaluated by a multidisciplinary group of experts to assess causality using the WHO-UMC system or the CIOMS/RUCAM score, for hepatic reactions. The public version of the WHO-Vigibase was also queried. RESULTS: From April 2002 to September 2015, out of 1261 total reports, 52 reports concerning 55 ARs to RYR dietary supplements were collected. ARs consisted in myalgia and/or increase in creatine phosphokinase (19), rhabdomyolysis (1), liver injury (10), gastrointestinal reactions (12), cutaneous reactions (9) and other reactions (4). Women were involved in 70% of cases. In 13 cases, the reaction required hospitalization, and 28 patients were taking other medications. Dechallenge was positive in 40 reactions (73%), rechallenge was positive in 7. Causality resulted as certain (1), probable (31, 56%), possible (18, 34%), unlikely (3) or unassessable (2). Similar distribution emerged from the WHO-Vigibase. CONCLUSIONS: The potential safety signals of myopathies and liver injury raise the hypothesis that the safety profile of RYR is similar to that of statins. Continuous monitoring of dietary supplements should be promoted to finally characterize their risk profile, thus supporting regulatory bodies for appropriate actions.

Curcumin and Resveratrol in the Management of Cognitive Disorders: What is the Clinical Evidence?

A growing body of in vitro and in vivo evidences shows a possible role of polyphenols in counteracting neurodegeneration: curcumin and resveratrol are attractive substances in this regard. In fact, epidemiological studies highlight a neuroprotective effect of turmeric (rhizome of Curcuma longa L.), the main source of curcumin. Moreover, the consumption of red wine, the main source of resveratrol, has been related to a lower risk of developing dementia. In this review, we analyzed the published clinical trials investigating curcumin and resveratrol in the prevention or treatment of cognitive disorders. The ongoing studies were also described, in order to give an overview of the current search on this topic. The results of published trials (five for curcumin, six for resveratrol) are disappointing and do not allow to draw conclusions about the therapeutic or neuroprotective potential of curcumin and resveratrol. These compounds, being capable of interfering with several processes implicated in the early stages of dementia, could be useful in preventing or in slowing down the pathology. To this aim, an early diagnosis using peripheral biomarkers becomes necessary. Furthermore, the potential preventive activity of curcumin and resveratrol should be evaluated in long-term exposure clinical trials, using preparations with high bioavailability and that are well standardized.