An Overview of the Enhanced Effects of Curcumin and Chemotherapeutic Agents in Combined Cancer Treatments.

Due to the progressive ageing of the human population, the number of cancer cases is increasing. For this reason, there is an urgent need for new treatments that can prolong the lives of cancer patients or ensure them a good quality of life. Although significant progress has been made in the treatment of cancer in recent years and the survival rate of patients is increasing, limitations in the use of conventional therapies include the frequent occurrence of side effects and the development of resistance to chemotherapeutic agents. These limitations are prompting researchers to investigate whether combining natural agents with conventional drugs could have a positive therapeutic effect in cancer treatment. Several natural bioactive compounds, especially polyphenols, have been shown to be effective against cancer progression and do not exert toxic effects on healthy tissues. Many studies have investigated the possibility of combining polyphenols with conventional drugs as a novel anticancer strategy. Indeed, this combination often has synergistic benefits that increase drug efficacy and reduce adverse side effects. In this review, we provide an overview of the studies describing the synergistic effects of curcumin, a polyphenol that has been shown to have extensive cytotoxic functions against cancer cells, including combined treatment. In particular, we have described the results of recent preclinical and clinical studies exploring the pleiotropic effects of curcumin in combination with standard drugs and the potential to consider it as a promising new tool for cancer therapy.

Bioactive Polyphenols and Neuromodulation: Molecular Mechanisms in Neurodegeneration.

The interest in dietary polyphenols in recent years has greatly increased due to their antioxidant bioactivity with preventive properties against chronic diseases. Polyphenols, by modulating different cellular functions, play an important role in neuroprotection and are able to neutralize the effects of oxidative stress, inflammation, and apoptosis. Interestingly, all these mechanisms are involved in neurodegeneration. Although polyphenols display differences in their effectiveness due to interindividual variability, recent studies indicated that bioactive polyphenols in food and beverages promote health and prevent age-related cognitive decline. Polyphenols have a poor bioavailability and their digestion by gut microbiota produces active metabolites. In fact, dietary bioactive polyphenols need to be modified by microbiota present in the intestine before being absorbed, and to exert health preventive effects by interacting with cellular signalling pathways. This literature review includes an evaluation of the literature in English up to December 2019 in PubMed and Web of Science databases. A total of 307 studies, consisting of research reports, review articles and articles were examined and 146 were included. The review highlights the role of bioactive polyphenols in neurodegeneration, with a particular emphasis on the cellular and molecular mechanisms that are modulated by polyphenols involved in protection from oxidative stress and apoptosis prevention.

ARX regulates cortical intermediate progenitor cell expansion and upper layer neuron formation through repression of Cdkn1c.

Mutations in the Aristaless-related homeobox (ARX) gene are found in a spectrum of epilepsy and X-linked intellectual disability disorders. During development Arx is expressed in pallial ventricular zone (VZ) progenitor cells where the excitatory projection neurons of the cortex are born. Arx(-/Y) mice were shown to have decreased proliferation in the cortical VZ resulting in smaller brains; however, the basis for this reduced proliferation was not established. To determine the role of ARX on cell cycle dynamics in cortical progenitor cells, we generated cerebral cortex-specific Arx mouse mutants (cKO). The loss of pallial Arx resulted in the reduction of cortical progenitor cells, particularly the proliferation of intermediate progenitor cells (IPCs) was affected. Later in development and postnatally cKO brains showed a reduction of upper layer but not deeper layer neurons consistent with the IPC defect. Transcriptional profile analysis of E14.5 Arx-ablated cortices compared with control revealed that CDKN1C, an inhibitor of cell cycle progression, is overexpressed in the cortical VZ and SVZ of Arx KOs throughout corticogenesis. We also identified ARX as a direct regulator of Cdkn1c transcription. Together these data support a model where ARX regulates the expansion of cortical progenitor cells through repression of Cdkn1c.

Efficacy of piroxicam plus cisplatin-loaded PLGA nanoparticles in inducing apoptosis in mesothelioma cells.

PURPOSE: Combined treatment based on cisplatin-loaded Poly(D,L-lactic-co-glicolic)acid (PLGA) nanoparticles (NP-C) plus the NSAID piroxicam was used as novel treatment for mesothelioma to reduce side effects related to cisplatin toxicity. METHODS: PLGA nanoparticles were prepared by double emulsion solvent evaporation method. Particle size, drug release profile and in vitro cellular uptake were characterized by TEM, DLS, LC/MS and fluorescence microscopy. MSTO-211H cell line was used to analyse NP-C biological efficacy by FACS and protein analysis. RESULTS: Cisplatin was encapsulated in 197 nm PLGA nanoparticles with 8.2% drug loading efficiency and 47% encapsulation efficiency. Cisplatin delivery from nanoparticles reaches 80% of total encapsulated drug in 14 days following a triphasic trend. PLGA nanoparticles in MSTO-211H cells were localized in the perinuclear space NP-C in combination with piroxicam induced apoptosis using a final cisplatin concentration 1.75 fold less than free drug. Delivered cisplatin cooperated with piroxicam in modulating cell cycle regulators as caspase-3, p53 and p21. CONCLUSIONS: Cisplatin loaded PLGA nanoparticles plus piroxicam showed a good efficacy in exerting cytotoxic activity and inducing the same molecular apoptotic effects of the free drugs. Sustained cisplatin release allowed to use less amount of drug, decreasing toxic side effects. This novel approach could represent a new strategy for mesothelioma treatment.

Electroporation in Translational Medicine: From Veterinary Experience to Human Oncology.

Electroporation (EP) is a broadly accepted procedure that, through the application of electric pulses with appropriate amplitudes and waveforms, promotes the delivery of anticancer molecules in various oncology therapies. EP considerably boosts the absorptivity of targeted cells to anticancer molecules of different natures, thus upgrading their effectiveness. Its use in veterinary oncology has been widely explored, and some applications, such as electrochemotherapy (ECT), are currently approved as first-line treatments for several neoplastic conditions. Other applications include irreversible electroporation and EP-based cancer vaccines. In human oncology, EP is still mostly restricted to therapies for cutaneous tumors and the palliation of cutaneous and visceral metastases of malignant tumors. Fields where veterinary experience could help smooth the clinical transition to humans include intraoperative EP, interventional medicine and cancer vaccines. This article recapitulates the state of the art of EP in veterinary and human oncology, recounting the most relevant results to date.

Transcriptional profiling of endometriosis tissues identifies genes related to organogenesis defects.

Endometriosis is a common benign pathology, characterised by the presence of endometrial tissue outside the endometrial cavity with a prevalence of 10-15% in reproductive-aged women. The pathogenesis is not completely understood, and several theories have been proposed to explain the aetiology. Our group has recently described the presence of ectopic endometrium in a consistent number of human female foetuses analysed by autopsy, reinforcing the hypothesis that endometriosis may be generated by defects during the organogenesis of the female reproductive trait. Herein, in order to identify, at molecular level, changes involved in the disease, we compared the transcriptional profiling of ectopic endometrium with the corresponding eutopic one. Statistical analyses lead us to identify some genes specifically deregulated in the ectopic endometrium, that are involved in gonad developmental process or in wound healing process. Among them, we identified BMP4 and GREM1. BMP4 was never associated before to endometriosis and is involved in the mesoderm-Müllerian duct differentiation. GREM1 is needed for the initial step of the ureter growth and perhaps could possibly be involved in Müller ducts differentiation. These molecules might be related to the endometriosis aetiology since we showed that their expression is not related to the menstrual cycle phase both at RNA and at protein levels. These data support the theory that embryological defects could be responsible of the endometriosis generation.

Functional and pharmacodynamic evaluation of metronomic cyclophosphamide and docetaxel regimen in castration-resistant prostate cancer.

AIM: The aim of our study was to investigate the association of docetaxel and metronomic cyclophosphamide (CYC) in castration-resistant prostate cancer (CRPC). MATERIALS & METHODS: CRPC xenografts were established with PC3 cells. Mice were treated with a combination of CYC (50 mg/kg/day) and docetaxel (10-30 mg/kg/week) or with docetaxel alone. Docetaxel plasma levels were analyzed in patients receiving the drug alone or combined with CYC. RESULTS: Metronomic CYC is an effective adjuvant in blocking tumor growth in vivo, with comparable efficacy and less toxic effects compared with docetaxel treatment. CYC acts by downregulating cell proliferation and inducing apoptosis thorough upregulation of p21 and inhibition of angiogenesis. Finally, CYC increases docetaxel plasma levels in patients. CONCLUSION: Metronomic CYC exerts anti-tumoral effects in an in vivo model of prostate cancer and in patients with CRPC, and also increases the bioavailability of docetaxel. These results explain the favorable toxicity and activity profiles observed in patients treated with this regimen.

The Antioxidant Effect of Dietary Bioactives Arises from the Interplay between the Physiology of the Host and the Gut Microbiota: Involvement of Short-Chain Fatty Acids.

The maintenance of redox homeostasis is associated with a healthy status while the disruption of this mechanism leads to the development of various pathological conditions. Bioactive molecules such as carbohydrates accessible to the microbiota (MACs), polyphenols, and polyunsaturated fatty acids (PUFAs) are food components best characterized for their beneficial effect on human health. In particular, increasing evidence suggests that their antioxidant ability is involved in the prevention of several human diseases. Some experimental data indicate that the activation of the nuclear factor 2-related erythroid 2 (Nrf2) pathway-the key mechanism in the maintenance of redox homeostasis-is involved in the beneficial effects exerted by the intake of PUFAs and polyphenols. However, it is known that the latter must be metabolized before becoming active and that the intestinal microbiota play a key role in the biotransformation of some ingested food components. In addition, recent studies, indicating the efficacy of the MACs, polyphenols, and PUFAs in increasing the microbial population with the ability to yield biologically active metabolites (e.g., polyphenol metabolites, short-chain fatty acids (SCFAs)), support the hypothesis that these factors are responsible for the antioxidant action on the physiology of the host. The underlying mechanisms through which MACs, polyphenols, and PUFAs might influence the redox status have not been fully elucidated, but based on the efficacy of SCFAs as Nrf2 activators, their contribution to the antioxidant efficacy of dietary bioactives cannot be excluded. In this review, we aimed to summarize the main mechanisms through which MACs, polyphenols, and PUFAs can modulate the host's redox homeostasis through their ability to directly or indirectly activate the Nrf2 pathway. We discuss their probiotic effects and the role played by the alteration of the metabolism/composition of the gut microbiota in the generation of potential Nrf2-ligands (e.g., SCFAs) in the host's redox homeostasis.

Aglianico Grape Seed Semi-Polar Extract Exerts Anticancer Effects by Modulating MDM2 Expression and Metabolic Pathways.

Grapevine (Vitis vinifera L.) seeds are rich in polyphenols including proanthocyanidins, molecules with a variety of biological effects including anticancer action. We have previously reported that the grape seed semi-polar extract of Aglianico cultivar (AGS) was able to induce apoptosis and decrease cancer properties in different mesothelioma cell lines. Concomitantly, this extract resulted in enriched oligomeric proanthocyanidins which might be involved in determining the anticancer activity. Through transcriptomic and metabolomic analyses, we investigated in detail the anticancer pathway induced by AGS. Transcriptomics analysis and functional annotation allowed the identification of the relevant causative genes involved in the apoptotic induction following AGS treatment. Subsequent biological validation strengthened the hypothesis that MDM2 could be the molecular target of AGS and that it could act in both a p53-dependent and independent manner. Finally, AGS significantly inhibited tumor progression in a xenograft mouse model of mesothelioma, confirming also in vivo that MDM2 could act as molecular player responsible for the AGS antitumor effect. Our findings indicated that AGS, exerting a pro-apoptotic effect by hindering MDM2 pathway, could represent a novel source of anticancer molecules.

In vitro model of stromal and epithelial immortalized endometriotic cells.

Endometriosis is a relatively common chronic gynecologic disorder that usually presents with chronic pelvic pain or infertility. It results from implantation of endometrial tissue outside the uterine cavity. Despite its frequency and its impact on quality of life, the understanding of pathogenesis of endometriosis remains incomplete and its treatment remains controversial. In this work, we established a suitable in vitro model system of immortalized human endometriotic cell line taking advantage of the human telomerase reverse transcriptase. The results demonstrate that these cells retain the natural characteristics of endometrial cells in term of phenotype and of functional expression of estrogen and progesterone receptors, without chromosomal abnormalities. In conclusion, these cells are potentially useful as an experimental model to investigate endometriosis biology.

Organic extract of Geodia cydonium induces cell cycle block in human mesothelioma cells.

The serious side effects caused by chemotherapeutics and the development of cancer chemoresistance represent the most significant limitations in the treatment of cancer. Some alternative approaches have been developed in recent years, which are based on natural compounds, and have allowed important advances in cancer therapeutics. During the last 50 years, sponges have been considered a promising source of natural products from the marine environment, representing ~30% of all marine natural products. Among sponges, the Mediterranean species Geodia cydonium represents a potential source of these type of products with considerable biotechnological interest as pharmaceutical agents. The present study demonstrated the antiproliferative effect of an organic G. cydonium extract (GEOCYDO) against three human mesothelioma cell lines, MSTO-211H (MSTO), NCI-H2452 (NCI) and Ist-Mes2 (Mes2), which differ in their sensitivity (MSTO and NCI) and resistance (Mes2) to standard combined treatment with cisplatin and piroxicam. To this aim, the activity of the extract was evaluated by analyzing its effects on cell viability, cancer properties and cell cycle progression by means of colony formation assay, cell cycle analysis and protein expression analysis. The results revealed, in mesothelioma, this extract was able to reduce self-renewal, cell migration and it could induce cell cycle arrest in G0/G1 stage, thus blocking cell proliferation. In conclusion, to the best of our knowledge, the present results indicated for the first time that GEOCYDO can contain active compounds able to affect cell proliferation in mesothelioma, suggesting that it could be considered as a potential novel drug source for cancer treatment.

Novel approaches in cancer treatment: preclinical and clinical development of small non-coding RNA therapeutics.

Short or small interfering RNAs (siRNAs) and microRNA (miRNAs) are molecules similar in size and function able to inhibit gene expression based on their complementarity with mRNA sequences, inducing the degradation of the transcript or the inhibition of their translation.siRNAs bind specifically to a single gene location by sequence complementarity and regulate gene expression by specifically targeting transcription units via posttranscriptional gene silencing. miRNAs can regulate the expression of different gene targets through their imperfect base pairing.This process - known as RNA interference (RNAi) - modulates transcription in order to maintain a correct physiological environment, playing a role in almost the totality of the cellular pathways.siRNAs have been evolutionary evolved for the protection of genome integrity in response to exogenous and invasive nucleic acids such as transgenes or transposons. Artificial siRNAs are widely used in molecular biology for transient silencing of genes of interest. This strategy allows to inhibit the expression of any target protein of known sequence and is currently used for the treatment of different human diseases including cancer.Modifications and rearrangements in gene regions encoding for miRNAs have been found in cancer cells, and specific miRNA expression profiles characterize the developmental lineage and the differentiation state of the tumor. miRNAs with different expression patterns in tumors have been reported as oncogenes (oncomirs) or tumor-suppressors (anti-oncomirs). RNA modulation has become important in cancer research not only for development of early and easy diagnosis tools but also as a promising novel therapeutic approach.Despite the emerging discoveries supporting the role of miRNAs in carcinogenesis and their and siRNAs possible use in therapy, a series of concerns regarding their development, delivery and side effects have arisen.In this review we report the biology of miRNAs and siRNAs in relation to cancer summarizing the recent methods described to use them as novel therapeutic drugs and methods to specifically deliver them to cancer cells and overcome the limitations in the use of these molecules.

Microbial diversity in Mediterranean sponges as revealed by metataxonomic analysis.

Although the Mediterranean Sea covers approximately a 0.7% of the world's ocean area, it represents a major reservoir of marine and coastal biodiversity. Among marine organisms, sponges (Porifera) are a key component of the deep-sea benthos, widely recognized as the dominant taxon in terms of species richness, spatial coverage, and biomass. Sponges are evolutionarily ancient, sessile filter-feeders that harbor a largely diverse microbial community within their internal mesohyl matrix. In the present work, we firstly aimed at exploring the biodiversity of marine sponges from four different areas of the Mediterranean: Faro Lake in Sicily and "Porto Paone", "Secca delle fumose", "Punta San Pancrazio" in the Gulf of Naples. Eight sponge species were collected from these sites and identified by morphological analysis and amplification of several conserved molecular markers (18S and 28S RNA ribosomal genes, mitochondrial cytochrome oxidase subunit 1 and internal transcribed spacer). In order to analyze the bacterial diversity of symbiotic communities among these different sampling sites, we also performed a metataxonomic analysis through an Illumina MiSeq platform, identifying more than 1500 bacterial taxa. Amplicon Sequence Variants (ASVs) analysis revealed a great variability of the host-specific microbial communities. Our data highlight the occurrence of dominant and locally enriched microbes in the Mediterranean, together with the biotechnological potential of these sponges and their associated bacteria as sources of bioactive natural compounds.

Arx acts as a regional key selector gene in the ventral telencephalon mainly through its transcriptional repression activity.

The homeobox-containing gene Arx is expressed during ventral telencephalon development and required for correct GABAergic interneuron tangential migration from the ganglionic eminences to the olfactory bulbs, cerebral cortex and striatum. Its human ortholog is associated with a variety of neurological clinical manifestations whose symptoms are compatible with the loss of cortical interneurons and altered basal ganglia-related activities. Herein, we report the identification of a number of genes whose expression is consistently altered in Arx mutant ganglionic eminences. Our analyses revealed a striking ectopic expression in the ganglionic eminences of several of these genes normally at most marginally expressed in the ventral telencephalon. Among them, Ebf3 was functionally analyzed. Thus, its ectopic expression in ventral telencephalon was found to prevent neuronal tangential migration. Further, we showed that Arx is sufficient to repress Ebf3 endogenous expression and that its silencing in Arx mutant tissues partially rescues tangential cell movement. Together, these data provide new insights into the molecular pathways regulated by Arx during telencephalon development.

Ginkgo biloba Prevents Oxidative Stress-Induced Apoptosis Blocking p53 Activation in Neuroblastoma Cells.

Oxidative stress has been associated to neuronal cell loss in neurodegenerative diseases. Neurons are post-mitotic cells that are very sensitive to oxidative stress-especially considering their limited capacity to be replaced. Therefore, reduction of oxidative stress, and inhibiting apoptosis, will potentially prevent neurodegeneration. In this study, we investigated the neuroprotective effect of Ginkgo biloba extract (EGb 761) against H2O2 induced apoptosis in SK-N-BE neuroblastoma cells. We analysed the molecular signalling pathway involved in the apoptotic cell death. H2O2 induced an increased acetylation of p53 lysine 382, a reduction in mitochondrial membrane potential, an increased BAX/Bcl-2 ratio and consequently increased Poly (ADP-ribose) polymerase (PARP) cleavage. All these effects were blocked by EGb 761 treatment. Thus, EGb 761, acting as intracellular antioxidant, protects neuroblastoma cells against activation of p53 mediated pathway and intrinsic mitochondrial apoptosis. Our results suggest that EGb 761, protecting against oxidative-stress induced apoptotic cell death, could potentially be used as nutraceutical for the prevention and treatment of neurodegenerative diseases.

Curcumin, Gut Microbiota, and Neuroprotection.

Curcumin, a nontoxic, naturally occurring polyphenol, has been recently proposed for the management of neurodegenerative and neurological diseases. However, a discrepancy exists between the well-documented pharmacological activities that curcumin seems to possess in vivo and its poor aqueous solubility, bioavailability, and pharmacokinetic profiles that should limit any therapeutic effect. Thus, it is possible that curcumin could exert direct regulative effects primarily in the gastrointestinal tract, where high concentrations of curcumin are present after oral administration. Indeed, a new working hypothesis that could explain the neuroprotective role of curcumin despite its limited availability is that curcumin acts indirectly on the central nervous system by influencing the "microbiota-gut-brain axis", a complex bidirectional system in which the microbiome and its composition represent a factor which preserves and determines brain "health". Interestingly, curcumin and its metabolites might provide benefit by restoring dysbiosis of gut microbiome. Conversely, curcumin is subject to bacterial enzymatic modifications, forming pharmacologically more active metabolites than curcumin. These mutual interactions allow to keep proper individual physiologic functions and play a key role in neuroprotection.

Curcumin C3 complex®/Bioperine® has antineoplastic activity in mesothelioma: an in vitro and in vivo analysis.

BACKGROUND: A major limitation in the treatment for malignant mesothelioma is related to serious side effects caused by chemotherapeutics and to the development of cancer-resistance. Advances in cancer therapies have been reached thanks to the introduction of alternative approaches, such as the use of phytochemicals. Curcumin-C3complex®/Bioperine® is a commercially standardized extract containing a ratio-defined mixture of three curcuminoids and piperine that greatly increase its bioavailability. Interestingly, the anticancer effect of this formulation has been described in different studies and several clinical trials have been started, but to our knowledge none refers to human mesothelioma. METHODS: Curcumin-C3complex®/Bioperine® anticancer effect was evaluated in vitro in different human mesothelioma cell lines analysing cell proliferation, colony-forming assay, wound healing assays, invasion assay and FACS analysis. In vivo anticancer properties were analysed in a mesothelioma xenograft mouse model in CD1 Nude mice. RESULTS: Curcumin-C3complex®/Bioperine® in vitro induced growth inhibition in all mesothelioma cell lines analysed in a dose- and time-depended manner and reduced self-renewal cell migration and cell invasive ability. Cell death was due to apoptosis. The analysis of the molecular signalling pathway suggested that intrinsic apoptotic pathway is activated by this treatment. This treatment in vivo delayed the growth of the ectopic tumours in a mesothelioma xenograft mouse model. CONCLUSIONS: Curcumin-C3complex®/Bioperine® treatment strongly reduces in vitro tumorigenic properties of mesothelioma cells by impairing cellular self-renewal ability, proliferative cell rate and cell migration and delays tumor growth in xenograft mouse model by reducing angiogenesis and increasing apoptosis. Considering that curcumin in vivo synergizes drug effects, its administration to treatment regimen may help to enhance drug therapeutic efficacy in mesothelioma. Our results suggest that implementation of standard pharmacological therapies with novel compounds may pave the way to develop alternative approaches to mesothelioma.

Polyphenols-gut microbiota interplay and brain neuromodulation.

Increasing evidence suggests that food ingested polyphenols can have beneficial effects in neuronal protection acting against oxidative stress and inflammatory injury. Moreover, polyphenols have been reported to promote cognitive functions. Biotransformation of polyphenols is needed to obtain metabolites active in brain and it occurs through their processing by gut microbiota. Polyphenols metabolites could directly act as neurotransmitters crossing the blood-brain barrier or indirectly by modulating the cerebrovascular system. The microbiota-gut-brain axis is considered a neuroendocrine system that acts bidirectionally and plays an important role in stress responses. The metabolites produced by microbiota metabolism can modulate gut bacterial composition and brain biochemistry acting as neurotransmitters in the central nervous system. Gut microbiota composition can be influenced by dietary ingestion of natural bioactive molecules such as probiotics, prebiotics and polyphenol. Microbiota composition can be altered by dietary changes and gastrointestinal dysfunctions are observed in neurodegenerative diseases. In addition, several pieces of evidence support the idea that alterations in gut microbiota and enteric neuroimmune system could contribute to onset and progression of these age-related disorders. The impact of polyphenols on microbiota composition strengthens the idea that maintaining a healthy microbiome by modulating diet is essential for having a healthy brain across the lifespan. Moreover, it is emerging that they could be used as novel therapeutics to prevent brain from neurodegeneration.

New Therapeutic Drugs from Bioactive Natural Molecules: The Role of Gut Microbiota Metabolism in Neurodegenerative Diseases.

BACKGROUND: The gut-brain axis is considered a neuroendocrine system, which connects the brain and gastrointestinal tract and plays an important role in stress response. The homeostasis of gut-brain axis is important for health conditions and its alterations are associated to neurological disorders and neurodegenerative diseases. METHOD: We selected recent papers analysing the association among alterations in the homeostasis of the gut-brain axis and neurological disorders. In addition, we described how bioactive natural molecules - such as polyphenols - by influencing gut microbiota composition may help rescue neural signalling pathways impaired in neurodegenerative diseases. RESULTS: Recent studies show that gut microbiota is a dynamic ecosystem that can be altered by external factors such as diet composition, antibiotics or xenobiotics. Gut bacterial community plays a key role in maintaining normal brain functions. Metagenomic analyses have elucidated that the relationship between gut and brain, either in normal or in pathological conditions, reflects the existence of a "microbiota-gut-brain" axis. Gut microbiota composition can be influenced by dietary ingestion of probiotics or natural bioactive molecules such as prebiotics and polyphenols. Their derivatives coming from microbiota metabolism can affect both the gut bacterial composition and brain biochemistry. CONCLUSION: This review highlights the role of gut microbiota in regulating regulates brain biochemistry and the role of microbiota metabolites on neuropathologies. Dietary ingestion of probiotics, prebiotics and polyphenols affect gut microbiota composition underlining the key role played by specific metabolites not only in the gut microbiota composition but also in the brain health maintenance.

Concordant morphologic and gene expression data show that a vaccine halts HER-2/neu preneoplastic lesions.

While much experimental data shows that vaccination efficiently inhibits a subsequent challenge by a transplantable tumor, its ability to inhibit the progress of autochthonous preneoplastic lesions is virtually unknown. In this article, we show that a combined DNA and cell vaccine persistently inhibits such lesions in a murine HER-2/neu mammary carcinogenesis model. At 10 weeks of age, all of the ten mammary gland samples from HER-2/neu-transgenic mice displayed foci of hyperplasia that progressed to invasive tumors. Vaccination with plasmids coding for the transmembrane and extracellular domain of rat p185neu followed by a boost with rp185neu+ allogeneic cells secreting IFN-gamma kept 48% of mice tumor free. At 22 weeks, their mammary glands were indistinguishable from those of 10-week-old untreated mice. Furthermore, the transcription patterns of the two sets of glands coincided. Of the 12,000 genes analyzed, 17 were differentially expressed and related to the antibody response. The use of B cell knockout mice as well as the concordance of morphologic and gene expression data demonstrated that the Ab response is the main mechanism facilitating tumor growth arrest. This finding suggests that a new way can be found to secure the immunologic control of the progression of HER-2/neu preneoplastic lesions.