Study on the activation of cell death mechanisms: in search of new therapeutic targets in glioblastoma multiforme.

Malignant primary brain tumors remain among the most difficult cancers to treat, in particular, Glioblastoma Multiforme (GBM) is the deadliest brain tumor. The standard therapies currently used are not efficient enough in improving patients' survival and quality of life. Cisplatin (CDDP), a platinum-based drug, has shown efficacy against different solid neoplasms, but it is also associated to different forms of off-target toxicity. To overcome the limitation in the use of CDDP in the treatment of GBM patients, fourth generation platinum compounds are been synthesized, one of them is the Pt(IV)Ac-POA, a prodrug with a medium-chain fatty acid as axial ligand, which acts as a histone 3 deacetylase inhibitor. Moreover, recently, the antioxidant effects of medicinal mushrooms have been shown to induce a lowering of the toxicity of chemotherapy drugs, inducing greater therapeutic efficiency, thus the combined therapy of chemotherapy and micotherapy could be helpful in the treatment of GBM reducing the adverse effects of the former thanks to phytotherapy's antioxidant, anti-inflammatory, immunomodulatory and antitumoral activities. Here, through immunoblotting, ultrastructural and immunofluorescence analysis, we evaluated the contribution in the activation of different cell death pathway of Micotherapy U-Care, a medicinal blend supplement, used together with platinum-based compounds on human glioblastoma U251 cells.

Cognitive Healthy Aging in Mice: Boosting Memory by an Ergothioneine-Rich Hericium erinaceus Primordium Extract.

Brain aging is a crucial risk factor for several neurodegenerative disorders and dementia. The most affected cognitive function is memory, worsening early during aging. Inflammation and oxidative stress are known to have a role in pathogenesis of cognitive impairments, and a link exists between aging/frailty and immunosenescence/inflammaging. Based on anti-aging properties, medicinal mushrooms represent a source to develop medicines and functional foods. In particular, Hericium erinaceus (He) displays several actions ranging from boosting the immune system to fighting senescence, due to its active ingredients/metabolites. Among these, Ergothioneine (ERGO) is known as the longevity vitamin. Currently, we demonstrated the efficacy of an ERGO-rich He primordium extract (He2) in preventing cognitive decline in a murine model of aging. We focused on recognition memory deterioration during aging, monitored through spontaneous behavioral tests assessing both memory components and frailty index. A parallel significant decrease in key markers of inflammation and oxidative stress, i.e., IL6, TGFß1, GFAP, Nrf2, SOD1, COX2, NOS2, was revealed in the hippocampus by immunohistochemistry, accompanied by an enhancement of NMDAR1and mGluR2, crucially involved in glutamatergic neurotransmission. In summary, we disclosed a selective, preventive and neuroprotective effect of He2 on aged hippocampus, both on recognition memory as well on inflammation/oxidative stress/glutamate receptors expression.

Voghera Sweet Pepper: A Potential Ally against Oxidative Stress and Aging.

In the present study, the potential functional properties of the extracts from the edible part of Capsicum annuum L. var. Peperone di Voghera (VP) were studied. The phytochemical analysis revealed a high amount of ascorbic acid, paralleled by a low carotenoid content. Normal human diploid fibroblasts (NHDF) were chosen as the in vitro model models to investigate the effects of the VP extract on oxidative stress and aging pathways. The extract of Carmagnola pepper (CP), another important Italian variety, was used as the reference vegetable. The cytotoxicity evaluation was performed firstly, using a 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay, while the VP potential antioxidant and antiaging activity was investigated by immunofluorescence staining focusing on specifically selected proteins. The MTT data revealed the highest cell viability at a concentration of up to 1 mg/mL. The immunocytochemical analyses highlighted an increased expression of transcription factors and enzymes involved in redox homeostasis (Nrf2, SOD2, catalase), improved mitochondrial functionality, and the up-regulation of the longevity gene SIRT1. The present results supported the functional role of the VP pepper ecotype, suggesting a feasible use of its derived products as valuable food supplements.

Fighting secondary triple-negative breast cancer in cerebellum: A powerful aid from a medicinal mushrooms blend.

Breast cancer (BC) is the second most common cause of brain metastasis onset in patients, with the cerebellum accounting for the 33% of cases. In the current study, using a 4T1 triple-negative mouse BC model, we revealed that an orally administered medicinal mushrooms (MM) blend, rich in ß-glucans, played a direct and specific anti-cancer action on cerebellar metastases, also bettering locomotor performances. The neuroprotective effect of the MM blend plays through (i) a direct and specific inhibition of cerebellar metastatization pattern typical of TNBC (with an induced reduction of about 50% of metastases density) and (ii) the regulation of apoptosis and proliferation-related genes, as suggested by expression changes of specific molecular markers, i.e. PCNA, p53, Bcl2, BAX, CASP9, CASP3, Hsp70 and AIF. Therefore, inhibiting the metastatization process, triggering a significant apoptosis increase, and lessening cell proliferation, this MM supplement, employed as adjuvant treatment in association with conventional therapy, could represent a promising approach, in the field of Integrative Oncology, for patients' management in both prevention and treatment of brain metastases from BC.

The power of a novel combined anticancer therapy: challenge and opportunity of micotherapy in the treatment of Glioblastoma Multiforme.

Glioblastoma (GBM) is the most common and mortal primary brain tumor in human. After standard therapies, that include surgical resection followed by radiotherapy and chemotherapy, it is difficult to completely remove the tumor and the development of relapses and resistance is almost inevitable. The chemotherapy now available also show important side effects, to overcame those limitation, new platinum-based drugs are being synthetized, Pt(IV)Ac-POA, (OC-6-44)-acetate-diamine-chloride(2-(2-propynyl)octanoato)platinum(IV), a prodrug having an Histone-3-DeAcetylase-Inhibitor as axial ligands, is one of them. Moreover, new compounds of plant origin are increasingly seen as potential sources of benefits in oncological treatments. The aim of the study is to investigate the possible contribution of micotherapy in the fight against GBM, its role in the metabolism of reactive oxygen species (ROS) and its synergic effect with a new platinum-based compound, Pt(IV)Ac-POA, on human glioblastoma U251 cells. Through cytofluorimetric and immunofluorescence analysis, the ability of the micotherapy in study to regulate the cell cycle was assessed, and its importance in controlling the cellular redox state was also revealed, opening to the possibility of a new therapy in which micotherapy can support the activity of new chemotherapy while reducing its side effects controlling inflammatory conditions in the microenvironment. Additionally, the combined therapy appeared able to induce regulated form of necrosis, such as ferroptosis, and to hinder the establishment of resistance mechanisms.

Searching for a Longevity Food, We Bump into Hericium erinaceus Primordium Rich in Ergothioneine: The "Longevity Vitamin" Improves Locomotor Performances during Aging.

Phenotypic frailty is characterized by a progressive decline in physical functioning. During ageing, morphological and functional alterations involve the brain, and chief theories involve oxidative stress, free radical accumulation, and reduced antioxidant defenses as the most implicated mechanisms. From boosting the immune system to fighting senescence, medicinal mushrooms have been found to have a number of health and longevity benefits. Among them, Hericium erinaceus (He) has been demonstrated to display a variety of physiological effects, including anti-aging properties. Thus, He represents an attractive natural source for developing novel medicines and functional foods, based on the identification of its active ingredients and metabolites. Particularly, H. erinaceus primordium (He2) extract contains a high amount of Ergothioneine (ERGO), the longevity vitamin. Herein, we revealed the preventive effect of ERGO-rich He2 extract in a preclinical model, focusing on locomotor decline during ageing monitored through spontaneous behavioral test. This effect was accompanied by a significant decrease in some oxidative stress markers (NOS2, COX2) paralleled by an increase in P53, showed in cerebellar cortex cells and fibres by immunohistochemistry. In summary, we demonstrated the neuro-protective and preventive effects of He2 extract during aging, probably due to its peculiarly high ERGO content.

Effects of Vitamin D Supplefmentation on Outcome of Low-Calorie Diet in Workers Presenting Obesity or Overweight: A Retrospective Observational Study.

AIM: Growing evidence underscores the inverse association between serum vitamin D (vit D) and chronic conditions such as metabolic syndrome, diabetes and obesity. The aim of this retrospective study was to compare weight loss and metabolic serum biomarkers in subjects on low-calorie diet receiving vit D supplementation versus those not receiving it. METHODS: The study considered 405 indoor sedentary workers with overweight/obesity and vit D insufficiency, who participated to a health fitness program between 2011-2013. Participants were recommended a moderately-low calorie diet plus vit D supplementation with 150,000 or 900,000 IU cumulative over 6 months in case of hypovitaminosis D (according to the guidelines at the enrollment), while those with optimal levels were recommended only diet. Participants were evaluated at baseline (T0), and after 6 months (T1). Anthropometric parameters, BMI, waist circumference (WC), serum 25-hydroxyvitamin D concentration ([25(OH)D]) and glycated hemoglobin (HbA1c) were assessed at T0 and T1. RESULTS: Participants fell into one of three groups: (A) not supplemented, (B) receiving 150,000 IU and (C) receiving 900,000 IU cumulative over 6 months. Overall, the supplementation was associated with increased [25(OH)D], but only the dosage of group C was associated with the achievement of optimal vit D status. A significantly greater weight decrease was observed in group B (-4.1 kg) and C (-4.5 kg) compared to untreated (-1.2 kg). WC reduction was higher in the vit D groups (group B: -3.95 cm; group C; -6.20 cm; untreated: -3.21 cm; p < 0.05). When setting the threshold for obesity at BMI > 30kg/m2, [25(OH)D] no longer correlated with body fat or weight. [25(OH)D] inversely correlated with the Homeostatic Model Assessment for Insulin Resistance and remained significant after adjustment for BMI. CONCLUSIONS: Higher [25(OH)D] levels were associated to a greater weight loss and enhanced the beneficial effects of a reduced-calorie diet in individuals with BMI > 30 kg/m2.

Neuroprotective Metabolites of Hericium erinaceus Promote Neuro-Healthy Aging.

Frailty is a geriatric syndrome associated with both locomotor and cognitive decline, typically linked to chronic systemic inflammation, i.e., inflammaging. In the current study, we investigated the effect of a two-month oral supplementation with standardized extracts of H. erinaceus, containing a known amount of Erinacine A, Hericenone C, Hericenone D, and L-ergothioneine, on locomotor frailty and cerebellum of aged mice. Locomotor performances were monitored comparing healthy aging and frail mice. Cerebellar volume and cytoarchitecture, together with inflammatory and oxidative stress pathways, were assessed focusing on senescent frail animals. H. erinaceus partially recovered the aged-related decline of locomotor performances. Histopathological analyses paralleled by immunocytochemical evaluation of specific molecules strengthened the neuroprotective role of H. erinaceus able to ameliorate cerebellar alterations, i.e., milder volume reduction, slighter molecular layer thickness decrease and minor percentage of shrunken Purkinje neurons, also diminishing inflammation and oxidative stress in frail mice while increasing a key longevity regulator and a neuroprotective molecule. Thus, our present findings demonstrated the efficacy of a non-pharmacological approach, based on the dietary supplementation using H. erinaceus extract, which represent a promising adjuvant therapy to be associated with conventional geriatric treatments.

Fibromyalgia and Nutrition: An Updated Review.

Due to the lack of specific and standardized treatments for the management of fibromyalgia (FM), available evidence suggests a multidisciplinary approach, and nutrition represents an important therapeutic strategy. This work aims to update the relationship between FM and nutrition, through a review of more recent scientific evidence based on a systematic research on PubMed. Of 66 records initially identified, 26 studies were selected and included in the present work. Although there is not sufficient evidence for the efficacy of specific nutritional protocols, the examined papers indicate a potential role of selected nutrients, micronutrients and food components in managing FM symptoms. However, several concerns persist as nutritional status and/or nutritional integration can improve FM symptoms, without expecting to lead to a remission of the disease. The use of targeted nutritional supplements may be of some relevance for the management of FM, but the up to date evidence remains weak. It is advisable, thus, to perform further studies of higher quality.KEY TEACHING POINTSFibromyalgia (FM) is characterized by chronic and diffuse musculoskeletal pain, often associated with a large set of symptoms.The therapeutic approach of FM include pharmacological and non-pharmacological interventions. Among them, an important role is played by nutrition.Of 66 record screened, 12 studies were included in the present review and five of them were randomized controlled trials. Nevertheless, the overall quality of those trials was scarce.Literature concerning FM and nutritions is growing. However, little evidence suggests that nutrition and/or nutritional intervention play a significant role on FM severity.The results of this review underline the need to carry out clinical studies of higher quality and rigor, possibly RCTs, focused on the role of nutrition in the symptoms and/or severity of FM.

From a Medicinal Mushroom Blend a Direct Anticancer Effect on Triple-Negative Breast Cancer: A Preclinical Study on Lung Metastases.

Bioactive metabolites isolated from medicinal mushrooms (MM) used as supportive treatment in conventional oncology have recently gained interest. Acting as anticancer agents, they interfere with tumor cells and microenvironment (TME), disturbing cancer development/progression. Nonetheless, their action mechanisms still need to be elucidated. Recently, using a 4T1 triple-negative mouse BC model, we demonstrated that supplementation with Micotherapy U-Care, a MM blend, produced a striking reduction of lung metastases density/number, paralleled by decreased inflammation and oxidative stress both in TME and metastases, together with QoL amelioration. We hypothesized that these effects could be due to either a direct anticancer effect and/or to a secondary/indirect impact of Micotherapy U-Care on systemic inflammation/immunomodulation. To address this question, we presently focused on apoptosis/proliferation, investigating specific molecules, i.e., PARP1, p53, BAX, Bcl2, and PCNA, whose critical role in BC is well recognized. We revealed that Micotherapy U-Care is effective to influence balance between cell death and proliferation, which appeared strictly interconnected and inversely related (p53/Bax vs. Bcl2/PARP1/PCNA expression trends). MM blend displayed a direct effect, with different efficacy extent on cancer cells and TME, forcing tumor cells to apoptosis. Yet again, this study supports the potential of MM extracts, as adjuvant supplement in the TNBC management.

Novel Medicinal Mushroom Blend as a Promising Supplement in Integrative Oncology: A Multi-Tiered Study using 4T1 Triple-Negative Mouse Breast Cancer Model.

Although medicinal mushroom extracts have been proposed as promising anti-cancer agents, their precise impacts on metastatic breast cancer are still to be clarified. For this purpose, the present study exploited the effect of a novel medicinal mushroom blend, namely Micotherapy U-care, in a 4T1 triple-negative mouse breast cancer model. Mice were orally administered with Micotherapy U-care, consisting of a mixture of Agaricus blazei, Ophiocordyceps sinensis, Ganoderma lucidum, Grifola frondosa, and Lentinula edodes. The syngeneic tumor-bearing mice were generated by injecting 4T1 cells in both supplemented and non-supplemented mice. After sacrifice 25 days later, specific endpoints and pathological outcomes of the murine pulmonary tissue were evaluated. (i) Histopathological and ultrastructural analysis and (ii) immunohistochemical assessment of TGF-ß1, IL-6 and NOS2, COX2, SOD1 as markers of inflammation and oxidative stress were performed. The QoL was comparatively evaluated. Micotherapy U-care supplementation, starting before 4T1 injection and lasting until the end of the experiment, dramatically reduced the pulmonary metastases density, also triggering a decrease of fibrotic response, and reducing IL-6, NOS, and COX2 expression. SOD1 and TGF-ß1 results were also discussed. These findings support the valuable potential of Micotherapy U-care as adjuvant therapy in the critical management of triple-negative breast cancer.

Pharmacogenetic-Based Interactions between Nutraceuticals and Angiogenesis Inhibitors.

Background: Angiogenesis inhibitors (AIs) have become established as an effective cancer treatment. Whereas their interactions with antineoplastic drugs have extensively been investigated, little is known of the effect of their co-administration with nutraceuticals/dietary supplements (N/DSs), which are often self-prescribed. N/DSs comprise a wide range of products such as herbs, nutrients, vitamins, minerals, and probiotics. Assessment of their interactions with cancer drugs, particularly AIs, is hampered by the difficulty of gauging the amount of active substances patients actually take. Moreover, there is no agreement on which approach should be used to determine which N/DSs are most likely to influence AI treatment efficacy. We present a comprehensive review of the metabolic routes of the major AIs and their possible interactions with N/DSs. Methods: The PubMed and Cochrane databases were searched for papers describing the metabolic routes of the main AIs and N/DSs. Results: Data from the 133 studies thus identified were used to compile a diagnostic table reporting known and expected AI-N/DS interactions based on their metabolization pathways. AIs and N/DSs sharing the cytochrome P450 pathway are at risk of negative interactions. Conclusions: Recent advances in pharmacogenetics offer exceptional opportunities to identify prognostic and predictive markers to enhance the efficacy of individualized AI treatments. The table provides a guide to genotyping patients who are due to receive AIs and is a promising tool to prevent occult AI-N/DS interactions in poor metabolizers. N/DS use by cancer patients receiving AIs is a topical problem requiring urgent attention from the scientific community.

Hericium erinaceus Improves Mood and Sleep Disorders in Patients Affected by Overweight or Obesity: Could Circulating Pro-BDNF and BDNF Be Potential Biomarkers?

Epidemiological data indicate that subjects affected by obesity have an increased risk of developing mood disorders. The relationship between obesity and mood disorders is bidirectional. We assessed whether a Hericium erinaceus treatment improved depression, anxiety, sleep, and binge eating disorders after 8 weeks of supplementation in subjects affected by overweight or obesity under a low calorie diet regimen. Looking for a possible clinical biomarker, we assessed the serum balance between brain-derived neurotrophic factor (BDNF) and its precursor pro-BDNF before and after H. erinaceus supplementation. Seventy-seven volunteers affected by overweight or obesity were recruited at the offices of the Department of Preventive Medicine, Luigi Devoto Clinic of Work, Obesity Centre, at the IRCCS Foundation Policlinico Hospital of Milan (Italy). Patients were recruited only if they had a mood and/or sleep disorder and/or were binge eating as evaluated through self-assessment questionnaires. We used two different enzyme-linked immunosorbent assays kits to discriminate circulating levels of pro-BDNF and BDNF. Eight weeks of oral H. erinaceus supplementation decreased depression, anxiety, and sleep disorders. H. erinaceus supplementation improved mood disorders of a depressive-anxious nature and the quality of the nocturnal rest. H. erinaceus increased circulating pro-BDNF levels without any significant change in BDNF circulating levels.

Phylogenetic Comparison between Italian and Worldwide Hericium Species (Agaricomycetes).

A broad literature concerns the genus Hericium, mainly regarding the medicinal properties of H. erinaceus. Congeneric species of H. erinaceus have been poorly investigated. We collected basidiomata of H. alpestre, H. coralloides and H. erinaceus in Italy and isolated the corresponding mycelia in pure culture. Analysis of the respective internal transcribed spacer regions confirmed the morphological identification of the strains. Internal transcribed spacer sequences from the Italian strains were phylogenetically compared along with 64 other sequences available from Gen-Bank, the CBS Strain Database, and the European Nucleotide Archive (ENA) for the same Hericium . Geographic origin and host plant species were cross-checked using the above data banks. Bayesian phylogenetic analysis produced a phylogram that permitted good discrimination among Hericium species. It provides an updated phylogeny within the genus Hericium and a better understanding of affinity among the species analyzed. The main Hericium clade includes the following: the H. erinaceus group and the H. alpestre/H. coralloides group, where the two species cluster separately. This study also allowed us to differentiate the H. erinaceus group on a biogeographical basis. The phylogenetic comparison further confirms the importance of a joint morphological-molecular approach to avoid misidentification and to guarantee the quality of strains for further chemical and medicinal characterization.

The Gut-Brain Axis in Alzheimer's Disease and Omega-3. A Critical Overview of Clinical Trials.

Despite intensive study, neurodegenerative diseases remain insufficiently understood, precluding rational design of therapeutic interventions that can reverse or even arrest the progressive loss of neurological function. In the last decade, several theories investigating the causes of neurodegenerative diseases have been formulated and a condition or risk factor that can contribute is described by the gut-brain axis hypothesis: stress, unbalanced diet, and drugs impact altering microbiota composition which contributes to dysbiosis. An altered gut microbiota may lead to a dysbiotic condition and to a subsequent increase in intestinal permeability, causing the so-called leaky-gut syndrome. Herein, in this review we report recent findings in clinical trials on the risk factor of the gut-brain axis in Alzheimer's disease and on the effect of omega-3 supplementation, in shifting gut microbiota balance towards an eubiosis status. Despite this promising effect, evidences reported in selected randomized clinical trials on the effect of omega-3 fatty acid on cognitive decline in Alzheimer's disease are few. Only Mild Cognitive Impairment, a prodromal state that could precede the progress to Alzheimer's disease could be affected by omega-3 FA supplementation. We report some of the critical issues which emerged from these studies. Randomized controlled trials in well-selected AD patients considering the critical points underlined in this review are warranted.

Tooth grooves, occlusal striations, dental calculus, and evidence for fiber processing in an Italian eneolithic/bronze age cemetery.

OBJECTIVES: We conducted a systematic macroscopic and microscopic examination of occlusal and para-occlusal wear in a large dental sample (n = 3,014) from 217 individuals dated to the Early Bronze age site of Gricignano d'Aversa, Italy. We used macroscopic and microscopic techniques to document nondietary occlusal and para-occlusal wear and to analyze calculus inclusions in some of the teeth. In combining an analysis of the wear with the calculus inclusions we linked the specific wear to the likely fiber that was involved in producing it. MATERIALS AND METHODS: Teeth and their high resolution epoxy casts were analyzed through SEM and reflected light microscopes. Nineteen individuals (fifteen with activity induced dental modifications and four as a control sample) were examined for the presence of calculus inclusions. RESULTS: Activity induced dental modifications (AIDMs), notches, grooves and micro-striations, were found in the 62.2% of the adult females, in 21.2% of the adults of unknown sex and in a single male. We found the full spectrum of dental manipulations from very minor nonocclusal wear in some young individuals to severe attrition at the other extreme. The width of the striations and grooves, mostly on the upper incisors, suggests a craft activity involving fibers and thread production and manipulation. From the dental calculus of two females with grooves and striations, we extracted three fragments of fibers, identified as hemp (Cannabis, sp.). Previously from Gricignano woven hemp fibers were found on both surfaces of a metal blade associated with a male burial. DISCUSSION: This study found the co-occurrence of tooth AIDMs and the actual fibers preserved in the dental calculus. As more work is done analyzing dental calculus in a variety of humans, it is apparent that this biological material holds rich resources documenting non-dietary habits.

Dietary Supplementation of Lion's Mane Medicinal Mushroom, Hericium erinaceus (Agaricomycetes), and Spatial Memory in Wild-Type Mice.

Hericium erinaceus is an edible and medicinal mushroom with potential neuroprotective effects. The study of H. erinaceus has attracted considerable attention during the past 10 years, particularly with regard to its potential utility in the treatment of motor dysfunction, Alzheimer disease, and other forms of dementia. We previously determined that oral supplementation with H. erinaceus results in significant improvements in novelty-seeking behavior and novel object recognition in mice. In this study, H. erinaceus was added to the diets of wild-type mice for 2 months, and effects on spatial memory were evaluated by means of a Y maze and an object location task. We found that H. erinaceus increased general locomotor activity but had no effect on spatial memory. Thus, oral supplementation with H. erinaceus yields specific and selective improvements in recognition memory without altering spatial working memory, which supports the hypothesis that recognition memory can be modeled as a dual process. In this model, the perirhinal cortex supports the recognition of individual items as part of a circuit involved in familiarity with an encountered stimulus, whereas the hippocampus supports recollected associations and relationships between stimuli.

B-glucans from Grifola frondosa and Ganoderma lucidum in breast cancer: an example of complementary and integrative medicine.

Culinary and medicinal mushrooms are widely used in Asian countries, both as dietary supplements and as nutraceutical foods. They have recently become popular in Europe, as well, for their nutritional and health benefits. In particular, epidemiological studies conducted in Asia suggest that mushroom intake, together with other phytotherapy substances, protects against cancer, specifically gastrointestinal (GI) and breast cancers. Most of the data come from in vitro studies and in vivo experimental animal models. Therefore, in order to translate the updated knowledge to clinical research (i.e., from bench to bedside) a systematic translational research program should be initiated. Future randomized controlled trials comparing the effects of G. frondosa and G. lucidum on conventional treatment outcomes are warranted. The purpose of this review was to describe the emerging mechanisms of action of the mushrooms' anticancer functions which makes their use in clinical practice so promising. Clinical effects of mycotherapy (specifically, the use of Ganoderma lucidum and Grifola frondosa) on long-term survival, tumor response, host immune functions, inflammation, and QoL in cancer patients were also addressed. Adverse events associated with mycotherapy were also investigated. Emerging data point to a potential role of G. lucidum for modulating the carcinogenic potential of GI microbiota, which suggests a new complementary and integrated approach to breast cancer treatment.

Coffee Intake Decreases Risk of Postmenopausal Breast Cancer: A Dose-Response Meta-Analysis on Prospective Cohort Studies.

Aim: A dose-response meta-analysis was conducted in order to summarize the evidence from prospective cohort studies regarding the association between coffee intake and breast cancer risk. Methods: A systematic search was performed in electronic databases up to March 2017 to identify relevant studies; risk estimates were retrieved from the studies and linear and non-linear dose-response analysis modelled by restricted cubic splines was conducted. A stratified and subgroup analysis by menopausal and estrogen/progesterone receptor (ER/PR) status, smoking status and body mass index (BMI) were performed in order to detect potential confounders. Results: A total of 21 prospective studies were selected either for dose-response, the highest versus lowest category of consumption or subgroup analysis. The dose-response analysis of 13 prospective studies showed no significant association between coffee consumption and breast cancer risk in the non-linear model. However, an inverse relationship has been found when the analysis was restricted to post-menopausal women. Consumption of four cups of coffee per day was associated with a 10% reduction in postmenopausal cancer risk (relative risk, RR 0.90; 95% confidence interval, CI 0.82 to 0.99). Subgroup analyses showed consistent results for all potential confounding factors examined. Conclusions: Findings from this meta-analysis may support the hypothesis that coffee consumption is associated with decreased risk of postmenopausal breast cancer.

The Selective Interaction of Pistacia lentiscus Oil vs. Human Streptococci, an Old Functional Food Revisited with New Tools.

Pistacia lentiscus berry oil (LBO) represents a typical vegetal product of the Mediterranean basin that has been formally used in traditional cuisine for 100s of years. In addition to its interesting alimentary properties, this product could represent an interesting candidate in the field of research on the study of new anti-infective agents. In fact, in Mediterranean countries, lentisk oil still continues to be widely used in folk medicine for oral and skin affections, in particular, acute gingivitis, pediatric skin infections such as impetigo and foot plaques, and biofilm related infections often associated with Streptococcus spp. Following these observations, we have hypothesized a "lentisk oil-bacteria" interaction, placing particular emphasis on the different Streptococcal species involved in these oral and skin diseases. In accordance with this hypothesis, the use of standard antimicrobial-antibiofilm methods (MIC, MBC, MBIC) allowed the interesting behavior of these bacteria to be observed and, in this context, the response to lentisk oil appears to be correlated with the pathogenic profile of the considered microorganism. Two probiotic strains of S. salivarius K12/M18 appeared to be non-sensitive to this product, while a set of five different pathogenic strains (S. agalactiae, S. intermedius, S. mitis, S. mutans, S. pyogenes) showed a response that was correlated to the fatty acid metabolic pathway of the considered species. In fact, at different times of bacteria development, selective High Performance Liquid Chromatography analysis of the growth medium containing LBO detected a significant increase in free unsaturated fatty acids (UFAs) in particular oleic, palmitic and linoleic acids, which are already known for their antibacterial activity. In this context, we have hypothesized that LBO could be able to modulate the pathogen/probiotic rate in a Streptococcal population using the fatty acid metabolic pathway to help the probiotic strain. This hypothesis was strengthened by performing antibacterial testing with oleic acid and an in silico evaluation of the Streptococcal MCRA protein, an enzyme involved in the production of saturated fatty acids from UFA. These results show that LBO may have been used in ancient times as a "natural microbial modulating extract" in the prevention of biofilm- associated diseases.