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Current evidence suggests that aberrant crypt foci (ACF) can be used to evaluate agents for their potential colon carcinogenic activity. The aim of the present study was to determine whether senna pod extract (SE) itself induces ACF and tumors in the rat colon or increases the development of ACF and tumors induced by azoxymethane (AOM). A daily administration of SE 10 mg/kg by mouth for 13-28 weeks produced a weak laxative effect but did not itself cause the appearance of ACF or tumors. The numbers of ACF and tumors induced by AOM were, however, increased by a dose of SE (100 mg/kg) able to induce chronic diarrhea over three months. These results suggest that SE does not cause the appearance of ACF or tumors in the rat colon nor does it have a promoting effect when given to rats at a dose that produces laxation (10 mg/kg), whereas a diarrhogenic dose (100 mg/kg) increases the appearance of tumors induced by AOM.

Recent pharmacological research on milk whey, a byproduct of the dairy industry, has identified several therapeutic properties that could be exploited in modern medicine. In the present study, we investigated the anticancer effects of whey from Mediterranean buffalo (Bubalus bubalis) milk. The antitumour effect of delactosed milk whey (DMW) was evaluated using the HCT116 xenograft mouse model of colorectal cancer (CRC). There were no discernible differences in tumour growth between treated and untreated groups. Nevertheless, haematoxylin and eosin staining of the xenograft tissues showed clearer signs of different cell death in DMW-treated mice compared to vehicle-treated mice. Detailed biochemical and molecular biological analyses revealed that DMW was able to downregulate the protein expression levels of c-myc, phospho-Histone H3 (ser 10) and p-ERK. Moreover, DMW also activated RIPK1, RIPK3, and MLKL axis in tumour tissues from xenograft mice, thus, suggesting a necroptotic effect. The necroptotic pathway was accompanied by activation of the apoptotic pathway as revealed by increased expression of both cleaved caspase-3 and PARP-1. At the molecular level, DMW-induced cell death was also associated with (i) upregulation of SIRT3, SIRT6, and PPAR-γ and (ii) downregulation of LDHA and PPAR-α. Overall, our results unveil the potential of whey as a source of biomolecules of food origin in the clinical setting of novel strategies for the treatment of CRC.

Objective to assess the inter-rater reliability (IRR) of the revised Cochrane risk-of-bias tool for randomised trials (RoB2). Methods Four raters independently applied RoB2 on critical and important outcomes of individually randomized parallel-group trials (RCTs) included in the Cochrane Review “Cannabis and cannabinoids for people with multiple sclerosis.” We calculated Fleiss’ Kappa for multiple raters and time to complete the tool; we performed a calibration exercise on five studies, then we developed an implementation document (ID) specific for the condition, and the intervention addressed by the review with instructions on how to answer the signalling questions of RoB2 tool. We measured IRR before and after the ID adoption Results Eighty results related to seven outcomes from 16 RCTs were assessed. During calibration exercise we reached no agreement for overall judgment (IRR -0.15); IRR for individual domains ranged from no agreement to fair. Mean time to apply the tool was 168.5 minutes per study. Time to complete the calibration exercise and develop the ID was about 40 hours. After the ID adoption ID, overall agreement increased to slightly (IRR 0.11) for the first five studies and moderate (IRR 0.42) for the remaining 11. IRR for individual domains ranged from no agreement to almost perfect. Mean time to apply the tool decreased to 41 minutes. Conclusion RoB2 tool is comprehensive but complex even for high experienced raters. The development of an ID specific for the review may improve reliability substantially.

Two diarylheptanoid heterodimers, zosterabisphenones A (1) and B (2), were isolated from the seagrass Zostera marina. They feature unprecedented catechol keto tautomers, stable because of steric constraints. Their structure elucidation was based on extensive low-temperature NMR studies and ECD and MS data, with the essential aid of DFT prediction of NMR and ECD spectra. Zosterabisphenone B (2) was selectively cytotoxic against the adenocarcinoma colon cancer cell line HCT116 with IC50 3.6 ± 1.1 μM at 48 h.

Background and Purpose: Transient receptor potential melastatin type-8 (TRPM8) is a cold-sensitive cation channel protein belonging to the TRP superfamily of ion channels. Here, we reveal the molecular mechanism of TRPM8 and its clinical relevance in colorectal cancer (CRC). Experimental Approach: TRPM8 expression and its correlation with the survival rate of CRC patients was analysed. To identify the key pathways and genes related to TRPM8 high expression, Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were conducted in CRC patients. TRPM8 functional role was assessed by using Trpm8−/− mice in models of sporadic and colitis-associated colon cancer. TRPM8 pharmacological targeting by WS12 was evaluated in murine models of CRC. Key Results: TRPM8 is overexpressed in colon primary tumours and in CD326+ tumour cell fraction. TRPM8 high expression was related to lower survival rate of CRC patients, Wnt–Frizzled signalling hyperactivation and adenomatous polyposis coli down-regulation. In sporadic and colitis-associated models of colon cancer, either absence or pharmacological desensitization of TRPM8 reduced tumour development via inhibition of the oncogenic Wnt/β-catenin signalling. TRPM8 pharmacological blockade reduced tumour growth in CRC xenograft mice by reducing the transcription of Wnt signalling regulators and the activation of β-catenin and its target oncogenes such as C-Myc and Cyclin D1. Conclusion and Implications: Human data provide valuable insights to propose TRPM8 as a prognostic marker with a negative predictive value for CRC patient survival. Animal experiments demonstrate TRPM8 involvement in colon cancer pathophysiology and its potential as a drug target for CRC.

ObjectiveTo summarise the available clinical evidence on the efficacy and safety of osteopathic manipulative treatment (OMT) for different conditions.DesignOverview of systematic reviews (SRs) and meta-analyses (MAs). PROSPERO CRD42020170983.Data sourcesAn electronic search was performed using seven databases: PubMed, EMBASE, CINAHL, Scopus, JBI, Prospero and Cochrane Library, from their inception until November 2021.Eligibility criteria for selecting studiesSRs and MAs of randomised controlled trials evaluating the efficacy and safety of OMT for any condition were included.Data extraction and synthesisThe data were independently extracted by two authors. The AMSTAR-2 tool was used to assess the methodological quality of the SRs and MAs. The overview was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.ResultsThe literature search revealed nine SRs or MAs conducted between 2013 and 2020 with 55 primary trials involving 3740 participants. The SRs reported a wide range of conditions including acute and chronic non-specific low back pain (NSLBP, four SRs), chronic non-specific neck pain (CNSNP, one SR), chronic non-cancer pain (CNCP, one SR), paediatric (one SR), neurological (primary headache, one SR) and irritable bowel syndrome (IBS, one SR). Although with a different effect size and quality of evidence, MAs reported that OMT is more effective than comparators in reducing pain and improving functional status in acute/chronic NSLBP, CNSNP and CNCP. Due to small sample size, presence of conflicting results and high heterogeneity, questionable evidence existed on OMT efficacy for paediatric conditions, primary headache and IBS.No adverse events were reported in most SRs. According to AMSTAR-2, the methodological quality of the included SRs was rated low or critically low.ConclusionBased on the currently available SRs and MAs, promising evidence suggests the possible effectiveness of OMT for musculoskeletal disorders. Limited and inconclusive evidence occurs for paediatric conditions, primary headache and IBS. Further well-conducted SRs and MAs are needed to confirm and extend the efficacy and safety of OMT.

Fish oil (FO) and phytocannabinoids have received considerable attention for their intestinal anti-inflammatory effects. We investigated whether the combination of FO with cannabigerol (CBG) and cannabidiol (CBD) or a combination of all three treatments results in a more pronounced intestinal antiinflammatory action compared to the effects achieved separately. Colitis was induced in mice by 2,4-dinitrobenzenesulfonic acid (DNBS). CBD and CBG levels were detected and quantified by liquid chromatography coupled with time of flight mass spectrometry and ion trap mass spectrometry (LC-MS-IT-TOF). Endocannabinoids and related mediators were assessed by LC-MS. DNBS increased colon weight/colon length ratio, myeloperoxidase activity, interleukin-1β, and intestinal permeability. CBG, but not CBD, given by oral gavage, ameliorated DNBS-induced colonic inflammation. FO pretreatment (at the inactive dose) increased the antiinflammatory action of CBG and rendered oral CBD effective while reducing endocannabinoid levels. Furthermore, the combination of FO, CBD, and a per se inactive dose of CBG resulted in intestinal anti-inflammatory effects. Finally, FO did not alter phytocannabinoid levels in the serum and in the colon. By highlighting the apparent additivity between phytocannabinoids and FO, our preclinical data support a novel strategy of combining these substances for the potential development of a treatment of inflammatory bowel disease.

ObjectivePrimary sclerosing cholangitis (PSC) is in 70% of cases associated with inflammatory bowel disease. The hypermorphic T108M variant of the orphan G protein-coupled receptor GPR35 increases risk for PSC and ulcerative colitis (UC), conditions strongly predisposing for inflammation-associated liver and colon cancer. Lack of GPR35 reduces tumour numbers in mouse models of spontaneous and colitis associated cancer. The tumour microenvironment substantially determines tumour growth, and tumour-associated macrophages are crucial for neovascularisation. We aim to understand the role of the GPR35 pathway in the tumour microenvironment of spontaneous and colitis-associated colon cancers.DesignMice lacking GPR35 on their macrophages underwent models of spontaneous colon cancer or colitis-associated cancer. The role of tumour-associated macrophages was then assessed in biochemical and functional assays.ResultsHere, we show that GPR35 on macrophages is a potent amplifier of tumour growth by stimulating neoangiogenesis and tumour tissue remodelling. Deletion of Gpr35 in macrophages profoundly reduces tumour growth in inflammation-associated and spontaneous tumour models caused by mutant tumour suppressor adenomatous polyposis coli. Neoangiogenesis and matrix metalloproteinase activity is promoted by GPR35 via Na/K-ATPase-dependent ion pumping and Src activation, and is selectively inhibited by a GPR35-specific pepducin. Supernatants from human inducible-pluripotent-stem-cell derived macrophages carrying the UC and PSC risk variant stimulate tube formation by enhancing the release of angiogenic factors.ConclusionsActivation of the GPR35 pathway promotes tumour growth via two separate routes, by directly augmenting proliferation in epithelial cells that express the receptor, and by coordinating macrophages’ ability to create a tumour-permissive environment.

A case of visceral Leishmaniasis in a renal transplant recipient is reported because of its peculiar clinical presentation: the presence of most clinical signs of the disease, such as high-grade fever, marked leucopenia, and splenomegaly, but persistent negativity of serology and of bone marrow smear. Forty days after the first bone marrow biopsy, the diagnosis was made possible by a second biopsy, and the treatment was started with antimonial compounds, which led to complete remission of symptoms. A relapse was observed 1 month after discontinuation of therapy, successfully treated with a new cycle of the same drug and allopurinol. The diagnosis of Leishmaniasis must always be considered in immunosuppressed transplant recipients with fever and leucopenia of unknown origin, even when serology and bone marrow smear are negative.

Background and purpose N-acylethanolamine acid amidase (NAAA) is a lysosomal enzyme accountable for the breakdown of N-acylethanolamides (NAEs) and its pharmacological inhibition determines beneficial effects in inflammatory conditions. The knowledge of NAAA in cancer is fragmentary with an unclarified mechanism whereas its contribution to colorectal cancer (CRC) is unknown to date. Experimental approach CRC xenograft and azoxymethane models assessed the in vivo pharmacological effect of NAAA inhibition; tumor secretome was evaluated by an oncogenic array; CRC cell lines were used for in vitro studies; cell cycle was analyzed by cytofluorimetry; NAAA was knocked down with siRNA; human biopsies were obtained from surgically resected CRC patients; gene expression was revealed by RT-PCR; NAEs were measured by LC-MS. Key results The NAAA inhibitor AM9053 reduced CRC xenograft tumor growth and counteracted tumor development in the azoxymethane model. NAAA inhibition impacted the composition of the tumor secretome that negatively affected the expression of epidermal growth factor family members. In CRC cells, AM9053 reduced proliferation with a mechanism mediated by PPAR-α and TRPV1 and induced cell cycle arrest in the S phase with cyclin A2/CDK2 downregulation. NAAA knock-down mirrored the effects of NAAA pharmacological inhibition. NAAA expression was downregulated in human CRC tissues, with a consequential augmentation of NAEs levels and dysregulation of some of their targets. Conclusions and implications Our results provide unprecedented data on the functional importance of NAAA in CRC progression and its mechanism. We propose this enzyme as a valid drug target for the treatment of CRC growth and development.

Background: Posttraumatic stress disorder (PTSD) is a psychiatric condition that manifests through a broad range of symptoms and shares several phenotypes with anxiety and depression. Refractory PTSD affects 10 – 30% of the patients and highlights the need for alternative pharmacotherapy. The suggested involvement of the endocannabinoid system (ECS) with the emotional processes has enlightened the use of Cannabis sp. Then, this study aimed to evaluate the therapeutic effects of a broad-spectrum Cannabis oil on anxiety- and depressive-like behaviors triggered by stressors from combined nature. In addition, this study investigated the effect of the oil on central cannabinoid receptor 1 and serum levels of cytokines, chemokines, and growth factors. Methods: Mice were randomized into five groups (vehicle; Cannabis oil; fluoxetine; single oral dose) and submitted to acute restraint and chronic unpredictable stress. Then, they were behaviorally assessed in the elevated plus-maze test (EPMT), forced swimming test (FST), splash test (ST), and open field test (OFT). The tetrad cannabinoid assay evaluated the central effect of the oil. Serum biomarkers levels were measured by a multiplex bead-based assay. Results: Cannabis oil (0.1 mg/kg, p.o.) significantly reduced the anxiety-like behavior in EPMT in the acute restraint stress model (p < 0.05) as compared to vehicle. Moreover, compared to the vehicle, Cannabis oil significantly reverted the despair and anhedonic-like behaviors in FST (p < 0.05) and ST (p < 0.05), respectively, in chronically stressed mice. Yet, compared to vehicle, therapy with Cannabis oil did not induce cannabinoid-tetrad (p < 0.0001); downregulated granulocyte-macrophage colony-stimulating factor (GM-CSF; p < 0.01) and advanced glycation end-products (RAGE; p < 0.0001); and upregulated vascular endothelial growth factor (VEGF; p < 0.01) serum levels. Conclusion: Altogether, our data suggest the potential of the broad-spectrum Cannabis oil to improve symptoms related to anxiety and depression caused by traumatic events.

Simple Summary Treatment of colon cancer remains a significant unmet need. Palmitoylethanolamide (PEA) is an endogenous fatty acid amide also present in food sources. PEA exerts intestinal anti-inflammatory effects, but knowledge of its role in colon carcinogenesis is still largely fragmentary. Here, we found that ultramicronized PEA inhibited tumor cell proliferation mediated by PPAR-α and GPR55, induced cell cycle arrest in the G2/M phase and DNA fragmentation, reduced cell migration and exerted beneficial effects in the azoxymethane model of colonic tumors. Collectively, these data provide evidence on the beneficial effects of PEA in colon carcinogenesis. Abstract Palmitoylethanolamide (PEA) is an endogenous fatty acid amide related to the endocannabinoid anandamide. PEA exerts intestinal anti-inflammatory effects, but knowledge of its role in colon carcinogenesis is still largely fragmentary. We deepened this aspect by studying the effects of PEA (ultramicronized PEA, um-PEA) on colon cancer cell proliferation, migration and cell cycle as well as its effects in a murine model of colon cancer. Results showed that um-PEA inhibited tumor cell proliferation via peroxisome proliferator-activated receptor α and G protein-coupled receptor 55, induced cell cycle arrest in the G2/M phase, possibly through cyclin B1/CDK1 upregulation, and induced DNA fragmentation. Furthermore, um-PEA reduced tumor cell migration by reducing MMP2 and TIMP1 expression. In vivo administration of um-PEA exerted beneficial effects in the azoxymethane model of colonic tumors, by reducing the number of preneoplastic lesions and tumors. Collectively, our findings provide novel proofs on the effects of um-PEA in colon carcinogenesis.

Experimental and clinical studies evidenced the health effects of moderate consumption of beer, mainly due to the presence of bioactive compounds, such as polyphenols, vitamins, or fibers. To exploit the potential beneficial effect on health and in disease prevention of these compounds, a new beverage based on barley malts and hops named Aliophen&reg, has been designed, through a patented production process, with a high total polyphenolic amount compared to alcohol-free beer and similar to the one present in light and dark beers. In the present study, the antioxidant activity of Aliophen&reg, against low-density lipoprotein (LDL) oxidation and its ability to protect erythrocytes from hemolysis have been characterized. Moreover, the chemopreventive effect of Aliophen&reg, against colon cancer has been assessed, employing a mouse model of chemically induced carcinogenesis using azoxymethane (AOM). Data obtained showed that Aliophen at a low dose (3 mg/kg) inhibited the formation of preneoplastic lesions, polyps, and tumors. At higher doses (300 mg/kg) the protective effect was measured in the first phase of the onset of cancer. The antioxidant properties of Aliophen&reg, were also observed in AOM-treated mice where it increased the serum antioxidant capacity. Based on the data presented, Aliophen&reg, can exert promising health effects, including an anticancer capacity presumably associated with its antioxidant properties.

In experimental colitis, administration of fish oil (FO) and the non-psychoactive cannabinoid, cannabidiol (CBD) reduces inflammation and ameliorates behavioural disturbances, two conditions associated with alterations in the gut microbiota (dysbiosis). We investigated the effect of combined FO/CBD administration on inflammation and dysbiosis in the dextran sulphate sodium (DSS) model of mouse colitis, which also causes behavioural disturbances. Colitis was induced in CD1 mice by 4% w/v DSS in drinking water for five consecutive days followed by normal drinking water. FO (20-75 mg/mouse) was administered once a day starting two days after DSS, whereas CBD (0.3-30 mg/kg), alone or after FO administration, was administered once a day starting three days after DSS, until day 8 (d8) or day 14 (d14). Inflammation was assessed at d8 and d14 (resolution phase) by measuring the Disease Activity Index (DAI) score, change in body weight, colon weight/length ratio, myeloperoxidase activity and colonic interleukin (IL)-1β (IL-1β), IL-10 and IL-6 concentrations. Intestinal permeability was measured with the fluorescein isothiocyanate-dextran. Behavioral tests (novel object recognition (NOR) and light/dark box test) were performed at d8. Fecal microbiota composition was determined by ribosomal 16S DNA sequencing of faecal pellets at d8 and d14. DSS-induced inflammation was stronger at d8 and accompanied by anxiety-like behaviour and impaired recognition memory at d8. FO (35, 50, 75 mg/mouse) alone reduced inflammation at d8, whereas CBD alone produced no effect at any of the doses tested; however, when CBD (3,10 mg/kg) was co-administered with FO (75 mg/mouse) inflammation was attenuated. FO (20 mg/mouse) and CBD (1 mg/kg) were ineffective when given alone, but when co-administered reduced all inflammatory markers and the impaired intestinal permeability at both d8 and d14 (but not the behavioural impairments). FO, CBD and their combination affected gut bacteria taxa that were not affected by DSS per se. Akkermansia muciniphila, a species suggested to afford anti-inflammatory action in colitis, was increased by DSS only at d14, but its levels were significantly elevated by all treatments at d8. FO and CBD co-administered at ineffective doses reduce colon inflammation, in a manner potentially strengthened by their independent elevation of Akkermansia muciniphila at d8.

This article belongs to the Special Issue Role of Nutraceuticals in Metabolic and Gastrointestinal Disorders., Cannabis sativa is an aromatic annual flowering plant with several botanical varieties, used for different purposes, like the production of fibers, the production of oil from the seeds, and especially for recreational or medical purposes. Phytocannabinoids (terpenophenolic compounds derived from the plant), include the well-known psychoactive cannabinoid Δ9 -tetrahydrocannabinol, and many non-psychoactive cannabinoids, like cannabidiol. The endocannabinoid system (ECS) comprises of endocannabinoid ligands, enzymes for synthesis and degradation of such ligands, and receptors. This system is widely distributed in the gastrointestinal tract, where phytocannabinoids exert potent effects, particularly under pathological (i.e., inflammatory) conditions. Herein, we will first look at the hemp plant as a possible source of new functional food ingredients and nutraceuticals that might be eventually useful to treat or even prevent gastrointestinal conditions. Subsequently, we will briefly describe the ECS and the general pharmacology of phytocannabinoids. Finally, we will revise the available data showing that non-psychoactive phytocannabinoids, particularly cannabidiol, may be useful to treat different disorders and diseases of the gastrointestinal tract. With the increasing interest in the development of functional foods for a healthy life, the non-psychoactive phytocannabinoids are hoped to find a place as nutraceuticals and food ingredients also for a healthy gastrointestinal tract function., This research was funded by CSIC, 201970E117.

Background: This review is an update of a previously published review in the Cochrane Database of Systematic Reviews (2009, Issue 3).Tea is one of the most commonly consumed beverages worldwide. Teas from the plant Camellia sinensis can be grouped into green, black and oolong tea, and drinking habits vary cross-culturally. C sinensis contains polyphenols, one subgroup being catechins. Catechins are powerful antioxidants, and laboratory studies have suggested that these compounds may inhibit cancer cell proliferation. Some experimental and nonexperimental epidemiological studies have suggested that green tea may have cancer-preventative effects. Objectives: To assess possible associations between green tea consumption and the risk of cancer incidence and mortality as primary outcomes, and safety data and quality of life as secondary outcomes. Search methods: We searched eligible studies up to January 2019 in CENTRAL, MEDLINE, Embase, ClinicalTrials.gov, and reference lists of previous reviews and included studies. Selection criteria: We included all epidemiological studies, experimental (i.e. randomised controlled trials (RCTs)) and nonexperimental (non-randomised studies, i.e. observational studies with both cohort and case-control design) that investigated the association of green tea consumption with cancer risk or quality of life, or both. Data collection and analysis: Two or more review authors independently applied the study criteria, extracted data and assessed methodological quality of studies. We summarised the results according to diagnosis of cancer type. Main results: In this review update, we included in total 142 completed studies (11 experimental and 131 nonexperimental) and two ongoing studies. This is an additional 10 experimental and 85 nonexperimental studies from those included in the previous version of the review. Eleven experimental studies allocated a total of 1795 participants to either green tea extract or placebo, all demonstrating an overall high methodological quality based on 'Risk of bias' assessment. For incident prostate cancer, the summary risk ratio (RR) in the green tea-supplemented participants was 0.50 (95% confidence interval (CI) 0.18 to 1.36), based on three studies and involving 201 participants (low-certainty evidence). The summary RR for gynaecological cancer was 1.50 (95% CI 0.41 to 5.48; 2 studies, 1157 participants; low-certainty evidence). No evidence of effect of non-melanoma skin cancer emerged (summary RR 1.00, 95% CI 0.06 to 15.92; 1 study, 1075 participants; low-certainty evidence). In addition, adverse effects of green tea extract intake were reported, including gastrointestinal disorders, elevation of liver enzymes, and, more rarely, insomnia, raised blood pressure and skin/subcutaneous reactions. Consumption of green tea extracts induced a slight improvement in quality of life, compared with placebo, based on three experimental studies. In nonexperimental studies, we included over 1,100,000 participants from 46 cohort studies and 85 case-control studies, which were on average of intermediate to high methodological quality based on Newcastle-Ottawa Scale 'Risk of bias' assessment. When comparing the highest intake of green tea with the lowest, we found a lower overall cancer incidence (summary RR 0.83, 95% CI 0.65 to 1.07), based on three studies, involving 52,479 participants (low-certainty evidence). Conversely, we found no association between green tea consumption and cancer-related mortality (summary RR 0.99, 95% CI 0.91 to 1.07), based on eight studies and 504,366 participants (low-certainty evidence). For most of the site-specific cancers we observed a decreased RR in the highest category of green tea consumption compared with the lowest one. After stratifying the analysis according to study design, we found strongly conflicting results for some cancer sites: oesophageal, prostate and urinary tract cancer, and leukaemia showed an increased RR in cohort studies and a decreased RR or no difference in case-control studies. Authors' conclusions: Overall, findings from experimental and nonexperimental epidemiological studies yielded inconsistent results, thus providing limited evidence for the beneficial effect of green tea consumption on the overall risk of cancer or on specific cancer sites. Some evidence of a beneficial effect of green tea at some cancer sites emerged from the RCTs and from case-control studies, but their methodological limitations, such as the low number and size of the studies, and the inconsistencies with the results of cohort studies, limit the interpretability of the RR estimates. The studies also indicated the occurrence of several side effects associated with high intakes of green tea. In addition, the majority of included studies were carried out in Asian populations characterised by a high intake of green tea, thus limiting the generalisability of the findings to other populations. Well conducted and adequately powered RCTs would be needed to draw conclusions on the possible beneficial effects of green tea consumption on cancer risk.

Marine-derived fungi are an important source of many valuable compounds with original structures and diverse physico-chemical properties. In this work, the metabolomic profile of a strain of Penicillium brevicompactum, recovered from a snakelocks sea anemone (Anemonia sulcata), was investigated through the parallel application of LC-ESI-HRMS, GC-MS, and NMR. Our strategy allowed the identification of mycophenolic acid, brevianamide A, and several compounds belonging to the thiosilvatins. Among the latter, five products are reported for the first time in this species. The main product of this series, cis-bis(methylthio)silvatin, was also tested for antiproliferative activity on both cancer and non-tumoral colon cell lines.

Nonprenylated rotenoids isolated from Boerhaavia diffusa are identified as new class of breast cancer resistance protein inhibitors (ABCG2). The recent determination of high-resolution structure of ABCG2 (with chemotherapeutics mitoxantrone or Ko143) enables the investigation of molecular interaction capacities of boeravinones. In this research pharmacokinetic/pharmacodynamic relationship of 17 boeravinones considering their molecular properties, ADMET profile and binding energies for ABCG2 was studied for the first time. All 17 compounds met the requirements of empirical rules for drug-likeness. Based on the obtained results lipophilicity was determined as the key property of boeravinones for the intestinal absorption, total clearance and acute and chronic toxicity in rats while polarity was the limiting factor for blood brain barrier permeation. Both lipophilicity and the fraction of sp3 hybridized carbon atoms influenced the binding affinity of boeravinones to ABCG2 proteins (6XVI and 6FFC) expressed as ChemPLP and GOLD Score. The performed in silico analysis implies that boeravinones could be used as potent safe leads to human ABCG2.

δ-Valerobetaine (δVB) is a constitutive milk metabolite with antioxidant and anti-inflammatory activities. Here, we tested the antineoplastic properties of milk δVB on human colorectal cancer cells. CCD 841 CoN (non-tumorigenic), HT-29 (p53 mutant adenocarcinoma) and LoVo (APC/RAS mutant adenocarcinoma) cells were exposed to 3 kDa milk extract, δVB (2 mM) or milk+δVB up to 72 h. Results showed a time- and dose-dependent capability of δVB to inhibit cancer cell viability, with higher potency in LoVo cells. Treatment with milk+δVB arrested cell cycle in G2/M and SubG1 phases by upregulating p21, cyclin A, cyclin B1 and p53 protein expressions. Noteworthy, δVB also increased necrosis (P P P SIRT6 silencing by small interfering RNA blocked autophagy and apoptosis activated by milk+δVB, unveiling the role of this sirtuin in the ROS-mediated apoptotic LoVo cell death.

Under physiological conditions, the small intestine represents a barrier against harmful antigens and pathogens. Maintaining of the intestinal barrier depends largely on cell&ndash, cell interactions (adherent-junctions) and cell&ndash, matrix interactions (tight-junctions). Inflammatory bowel disease is characterized by chronic inflammation, which induces a destructuring of the architecture junctional epithelial proteins with consequent rupture of the intestinal barrier. Recently, a peptide identified by Bubalus bubalis milk-derived products (MBCP) has been able to reduce oxidative stress in intestinal epithelial cells and erythrocytes. Our aim was to evaluate the therapeutic potential of MBCP in inflammatory bowel disease (IBD). We studied the effect of MBCP on (i) inflamed human intestinal Caco2 cells and (ii) dinitrobenzene sulfonic acid (DNBS) mice model of colitis. We have shown that MBCP, at non-cytotoxic concentrations, both in vitro and in vivo induced the adherent epithelial junctions organization, modulated the nuclear factor (NF)-&kappa, B pathway and reduced the intestinal permeability. Furthermore, the MBCP reverted the atropine and tubocurarine injury effects on adherent-junctions. The data obtained showed that MBCP possesses anti-inflammatory effects both in vitro and in vivo. These results could have an important impact on the therapeutic potential of MBCP in helping to restore the intestinal epithelium integrity damaged by inflammation.

Patients with ulcerative colitis (UC) using marijuana have been reported to experience symptomatic benefit. Cannabidivarin (CBDV) is a safe non-psychoactive phytocannabinoid able to activate and desensitize TRPA1, a member of the TRP channels superfamily, which plays a pivotal role in intestinal inflammation. Here, we have investigated the potential intestinal anti-inflammatory effect of CBDV in mice and in biopsies from pediatric patients with active UC. Colonic inflammation was induced in mice by dinitrobenzenesulfonic acid (DNBS). The effect of orally administered CBDV on macroscopic and microscopic damage, inflammatory parameters (i.e. myeloperoxidase activity, intestinal permeability and cytokine production) and faecal microbiota composition, was evaluated 3 days after DNBS administration. TRPA1 expression was studied by RT-PCR in inflamed colons of mice as well as in mucosal colonic biopsies of children with active UC, whose response to incubation with CBDV was also investigated. CBDV attenuates, in a TRPA1-antagonist sensitive manner, DNBS-induced signs of inflammation including neutrophil infiltration, intestinal permeability, and cytokine (i.e. IL-1β, IL-6 and the chemokine MCP-1) production. CBDV also alters the dysregulation of gut microbiota associated to colitis. Finally, CBDV lessens cytokine expression in colonic biopsies from pediatric patients with ulcerative colitis, a condition in which TRPA1 was up-regulated. Our preclinical study shows that CBDV exerts intestinal anti-inflammatory effects in mice via TRPA1, and in children with active UC. Since CBDV has a favorable safety profile in humans, it may be considered for possible clinical trials in patients with UC.