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Background and Aims: Intestinal fibrosis, a frequent complication of inflammatory bowel disease, is characterized by stricture formation with no pharmacological treatment to date. N-acylethanolamine acid amidase (NAAA) is responsible of acylethanolamides (AEs, e.g., palmitoylethanolamide and oleoylethanolamide) hydrolysis. Here, we investigated NAAA and AEs signalling in gut fibrosis., Methods: NAAA and AEs signalling were evaluated in human intestinal specimens from stenotic Crohn's diseases (CD) patients. Gut fibrosis was induced by TNBS, monitored by colonoscopy and unascertained by qRT-PCR, histological analyses, and confocal microscopy. Immune cells were analysed in mesenteric lymph nodes by FACS. Colonic fibroblasts were cultured in conditioned media derived from polarized or not bone marrow-derived macrophages (BMDM). IL-23 signalling was evaluated by qRT-PCR, ELISA, FACS, and western blot in BMDM and in lamina propria CX3CR1+ cells., Results: In ileocolonic human CD strictures, increased transcript expression of NAAA was observed with a decrease of its substrates OEA and PEA. NAAA inhibition reduced intestinal fibrosis in vivo, as revealed by decrease in inflammatory parameters, collagen deposition and fibrosis genes, including epithelial to mesenchymal transition. More in-depth studies revealed modulation of the immune response related to IL-23 following NAAA inhibition. The antifibrotic actions of NAAA inhibition are mediated by Mφ and M2 macrophages that indirectly affect fibroblast collagenogenesis. NAAA inhibitor AM9053 normalized IL-23 signalling in BMDM and in lamina propria CX3CR1+ cells., Conclusions: Our findings provide new insights into the pathophysiological mechanism of intestinal fibrosis and identify NAAA as a promising target for the development of therapeutic treatments to alleviate CD fibrosis., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Colorectal cancer (CRC) is one of the most common malignant tumours worldwide. Diarylheptanoids, secondary metabolites isolated from Zostera marina, are of interest in natural products research due to their biological activities. Zosterabisphenone B (ZBP B) has recently been shown to inhibit the viability of CRC cells. The aim of this study was to investigate the therapeutic potential of ZBP B for targeting human CRC cells. Cell viability was determined using the MTT assay. Flow cytometry and Western blot analyses were used to assess apoptosis and autophagy. A CRC xenograft model was used to evaluate the in vivo effect of ZBP B. No cytotoxic effect on HCEC cells was observed in the in vitro experiments. ZBP B caused morphological changes in HCT116 colon cancer cells due to an increase in early and late apoptotic cell populations. Mechanistically, ZBP B led to an increase in cleaved caspase-3, caspase-8, caspase-9, PARP and BID proteins and a decrease in Bcl-2 and c-Myc proteins. In the xenograft model of CRC, ZBP B led to a reduction in tumour growth. These results indicate that ZBP B exerts a selective cytotoxic effect on CRC cells by affecting apoptotic signalling pathways and reducing tumour growth in mice. Taken together, our results suggest that ZBP B could be a lead compound for the synthesis and development of CRC drugs., (© 2024 John Wiley & Sons Ltd.)

Hyperlipidaemia is a recognised risk factor for cardiovascular disease. In this study, the antihyperlipidaemic properties of spirulina (Arthrospira platensis, strain S2 from Serbia) were tested in adult Wistar rats before and after induction of hypercholesterolaemia by a high-fat diet (HFD) to compare the preventive with the curative effect. Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), alanine transaminase (ALT) and aspartate transaminase (AST) levels were measured in the blood samples. The chemical composition (lipids, proteins and cholesterol) and the content of bile acids in the faeces of the animals were also analysed. Feeding rats with an atherogenic diet for 10 weeks led to the successful development of hyperlipidaemia, as serum TC and LDL-C levels as well as lipids, cholesterol and bile acids in the animals' faeces were significantly increased. Pre- and post-treatment with spirulina led to a reduction in serum LDL, TC and ALT levels. Administration of spirulina resulted in both a significant increase in primary bile acids excretion and a decrease in bile acids metabolism, with pre-treatment being more effective than post-treatment in some cases. These results suggest that increased excretion of bile acids as well as an effect on the gut microbiota may be the mechanism responsible for the anti-hyperlipidaemic activity of the tested spirulina strain.

Parkinson's Disease (PD), a neurodegenerative disorder, is characterized by the degeneration of progressive dopaminergic (DA) neurons in the substantia nigra region of the human midbrain. Although just what causes PD remains a mystery, it is known that oxidative stress (OS) as well as mitochondrial dysfunction, neuro-inflammation, and insufficient neurotrophic support play a role in the disease's pathophysiology. Phytochemicals are a diverse small molecule group derived from plants that can be classified into numerous classes on the basis of their biological activities and chemical structure. Of these groups of phytochemicals, the most abundant, which has well-established anti-Parkinson's effects, are polyphenols. Flavonoids, including naringin and naringenin, genistein, kaempferol, anthocyanins, epigallocatechin-3-gallate, and baicalein are plant-based biologically active polyphenols, which have been shown to exhibit therapeutic potential when used as treatment for a variety of pathological illnesses, such as neurodegenerative diseases (NDs) and PD. Recently, it was reported that flavonoids have beneficial effects on PD, such as the protection of DA neurons, improvement of motor and cognitive abilities, regulation of signaling pathways, and modulation of OS and neuro-inflammation. In addition, by changing the composition of bacteria in gut microbiota, flavonoids reduce pathogenic strains and promote the growth of beneficial strains. In this context, the current paper will provide a literature review on the neurological roles that flavonoids play, as one of the most abundant phytochemical families, in PD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Ethnopharmacological Relevance: Chamomile (M. chamomilla L.) is an herbaceous plant from family Astereaceae, that has a long history of use in traditional medicine. It has been used as herbal remedies for thousands of years to treat several diseases, including infections, neuropsychiatric, respiratory, gastrointestinal, and liver disorders. Chronic inflammation is involved in the pathogenesis of most infectious and non-infectious diseases and macrophages are considered the major cellular players that drive disease initiation and maintenance., Aim of the Study: The aim of this study was to evaluate the variation in the chemical profile of the essential oil of M. chamomilla plants collected in three experimental field sites in the Molise region. Additionally, we evaluated the pharmacological mechanism behind the anti-inflammatory effect of M. chamomilla essential oils., Material and Methods: Three essential oils (called GC1, GC2 and GC3) were extracted from aerial parts of M. chamomilla by hydrodistillation and chemical composition was analyzed by gas chromatography-mass spectrometry (GC-MS). The essential oils were tested for their ability to modulate pro-inflammatory murine macrophages and human peripheral blood mononuclear cells (PBMCs) functions., Results: The chemical analysis of the samples revealed the presence of a high content of the oxygenated sesquiterpenes that represented more than the half of the entire oils. GC1, GC2 and GC3 essential oils significantly attenuated LPS/IFN-γ-induced inflammation by reducing M1 polarization. In details, they showed significant anti-inflammatory property by inhibiting NO, TNF-α and IL-6 production. These effects were correlated to a suppression of LPS-mediated p65 activation, the critical transactivation subunit for NF-κB transcription factor. Oxidative stress may trigger macrophages activation and elicit strong immune responses. Our study demonstrated that GC1, GC2 and GC3 were highly effective at increasing GCL and HMOX-1 anti-oxidant enzymes expression leading to the rapid scavenging of ROS. The antioxidant activity of these oils was explained throughout the activation of NRF2 signaling pathway. Next, we demonstrated that essential oils were able to reduce CD4 + T cell activation which are also involved in inflammatory processes., Conclusions: Our data describe for the first time that chamomile essential oils exerted their anti-inflammatory and antioxidant activity by modulating macrophages and CD4 + T cells-mediate immune response., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Analysis of extracts of the marine sponge Clathria faviformis by high-resolution LC-MS 2 and molecular networking resulted in the discovery of a new family of potentially UV-protecting phospholipids, the favilipids. One of them, favilipid A ( 1 ), was isolated and its structure determined by mass and tandem mass spectrometry, NMR, electronic circular dichroism (ECD), and computational studies. Favilipid A, which has no close analogues among natural products, possesses an unprecedented structure characterized by a 4-aminodihydropiridinium core, resulting in UV-absorbing properties that are very unusual for a phospholipid. Consequently, favilipid A could inspire the development of a new class of molecules to be used as sunscreen ingredients. In addition, favilipid A inhibited by 58-48% three kinases (JAK3, IKKβ, and SYK) involved in the regulation of the immune system, suggesting a potential use for treatment of autoimmune diseases, hematologic cancers, and other inflammatory states.

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., (© 2022 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The widespread seagrass Zostera marina contains a new diarylheptanoid heterodimer, zosterabisphenone C ( 1 ), featuring an unprecedented rearrangement of one of its benzene rings to a cyclopentenecarbonyl unit. The planar structure and absolute configuration of zosterabisphenone C were elucidated by a combination of spectroscopic (MS, ECD, and low-temperature NMR) and computational (DFT-NMR and DFT-ECD) evidence. Consistent with the previously isolated zosterabisphenones, compound 1 was selectively cytotoxic against HCT 116 adenocarcinoma colon cancer cells, reducing their viability by 73% at 10 μM (IC 50 of 7.6 ± 1.1 μM). The biosynthetic origin of zosterabisphenone C ( 1 ) from an oxidative rearrangement of zosterabisphenone A ( 4 ) is proposed.

Olive tree leaves are an abundant source of bioactive compounds with several beneficial effects for human health, including a protective role against many types of cancer. In this study, we investigated the effect of an extract, obtained from olive tree (Olea europaea L.) leaves (OLE), on proliferation, invasion, and epithelial to mesenchymal transition (EMT) on metastatic melanoma, the highly aggressive form of skin cancer and the deadliest diseases. Our results demonstrated that OLE inhibited melanoma cells proliferation through cell cycle arrest and induction of apoptotic cell death. Moreover, OLE suppressed the migration, invasion, and colonies formation of human melanoma cells. Similar to our in vitro findings, we demonstrated that the oral administration of OLE inhibited cutaneous tumor growth and lung metastasis formation in vivo by modulating the expression of EMT related factors. In addition, the anti-proliferative and anti-invasive effects of OLE against melanoma were also related to a simultaneous targeting of mitogen-activated protein kinase and PI3K pathways, both in vitro and in vivo. In conclusion, our findings suggest that OLE has the potential to inhibit the metastatic spread of melanoma cells thanks to its multifaceted mechanistic effects, and may represent a new add-on therapy for the management of metastatic melanoma., (© 2022 The Authors. Phytotherapy Research published by John Wiley & Sons Ltd.)

Malignant melanoma is the deadliest skin cancer, due to its propensity to metastasize. MAPKs and NF-κB pathways are constitutively activated in melanoma and promote cell proliferation, cell invasion, metastasis formation, and resistance to therapeutic regimens. Thus, they represent potential targets for melanoma prevention and treatment. Phytochemicals are gaining considerable attention for the management of melanoma because of their several cellular and molecular targets. A screening of a small library of sesquiterpenes lactones selected cynaropicrin, isolated from the aerial parts of Centaurea drabifolia subsp. detonsa, for its potential anticancer effect against melanoma cells. Treatment of human melanoma cells A375 with cynaropicrin resulted in inhibition of cell proliferation and induction of caspase-3-dependent apoptosis. Furthermore, cynaropicrin reduced several cellular malignant features such migration, invasion, and colonies formation through the inhibition of ERK1/2 and NF-κB activity. Cynaropicrin was able to reduce intracellular reactive oxygen species generation, which are involved in all the stages of carcinogenesis. Indeed, cynaropicrin increased the expression of several antioxidant genes, such as glutamate-cysteine ligase and heme oxygenase-1, by promoting the activation of the transcription factor Nrf-2. In conclusion, our results individuate cynaropicrin as a potential adjuvant chemotherapeutic agent for melanoma by targeting several protumorigenic signaling pathways., (© 2020 John Wiley & Sons Ltd.)

Olive tree ( Olea europaea L.) leaves are an abundant source of bioactive compounds with several beneficial effects for human health. Recently, the effect of olive leaf extract in obesity has been studied. However, the molecular mechanism in preventing obesity-related inflammation has not been elucidated. Obesity is a state of chronic low-grade inflammation and is associated with an increase of pro-inflammatory M1 macrophages infiltration in the adipose tissue. In the current study, we explored Olea europaea L. leaf extract (OLE) anti-inflammatory activity using an in vitro model of obesity-induced inflammation obtained by stimulating murine macrophages RAW 264.7 with high dose of the free fatty acid palmitate. We found that OLE significantly suppressed the induction of pro-inflammatory mediators, tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, nitric oxide (NO), prostaglandin E2 (PGE2) and reactive oxygen species (ROS), while it enhanced the anti-inflammatory cytokine, IL-10. Moreover, we demonstrated that OLE reduced the oxidative stress induced by palmitate in macrophages by regulating the NF-E2-related factor 2 (NRF2)-Kelch-like ECH-associated protein 1 (KEAP1) pathway. Finally, we showed that OLE promoted the shift of M1 macrophage toward less inflammatory M2-cells via the modulation of the associated NF-κB and proliferator-activated receptor gamma (PPARγ) signaling pathways. Thereby, our findings shed light on the potential therapeutic feature of OLE in recovering obesity-associated inflammation via regulating M1/M2 status.

Suppression of antitumor immune responses is one of the main mechanisms by which tumor cells escape from destruction by the immune system. Myeloid-derived suppressor cells (MDSCs) represent the main immunosuppressive cells present in the tumor microenvironment (TME) that sustain cancer progression. MDSCs are a heterogeneous group of immature myeloid cells with a potent activity against T-cell. Studies in mice have demonstrated that MDSCs accumulate in several types of cancer where they promote invasion, angiogenesis, and metastasis formation and inhibit antitumor immunity. In addition, different clinical studies have shown that MDSCs levels in the peripheral blood of cancer patients correlates with tumor burden, stage and with poor prognosis in multiple malignancies. Thus, MDSCs are the major obstacle to many cancer immunotherapies and their targeting may be a beneficial strategy for improvement the efficiency of immunotherapeutic interventions. However, the great heterogeneity of these cells makes their identification in human cancer very challenging. Since both the phenotype and mechanisms of action of MDSCs appear to be tumor-dependent, it is important to accurately characterized the precise MDSC subsets that have clinical relevance in each tumor environment to more efficiently target them. In this review we summarize the phenotype and the suppressive mechanisms of MDSCs populations expanded within different tumor contexts. Further, we discuss about their clinical relevance for cancer diagnosis and therapy., (Copyright © 2020 De Cicco, Ercolano and Ianaro.)

Background and Purpose: Myeloid-derived suppressor cells (MDSCs) represent a major obstacle to cancer treatment, as they negatively regulate anti-tumour immunity through the suppression of tumour-specific T lymphocytes. Thus, the efficacy of immunotherapies may be improved by targeting MDSCs. In this study, we assessed the ability of hydrogen sulfide (H 2 S), a gasotransmitter whose anti-cancer effects are well known, to inhibit the accumulation and immunosuppressive functions of MDSCs in melanoma., Experimental Approach: Effects of H 2 S on the host immune response to cancer were evaluated using an in vivo syngeneic model of murine melanoma. B16F10-melanoma-bearing mice were treated with the H 2 S donor, diallyl trisulfide (DATS) and analysed for content of MDSCs, dendritic cells (DCs) and T cells. Effects of H 2 S on expression of immunosuppressive genes in MDSCs and on T cell proliferation were evaluated., Key Results: In melanoma-bearing mice, DATS inhibited tumour growth, and this effect was associated with a reduction in the frequency of MDSCs in the spleen, in the blood as well as in the tumour micro-environment. In addition, we found that CD8 + T cells and DCs were increased. Furthermore, DATS reduced the immuno-suppressive activity of MDSCs, restoring T cell proliferation., Conclusions and Implications: The H 2 S donor compound, DATS, inhibited the expansion and the suppressive functions of MDSCs, suggesting a novel role for H 2 S as a modulator of MDSCs in cancer. Therefore, H 2 S donors may provide a novel approach for enhancing the efficacy of melanoma immunotherapy., Linked Articles: This article is part of a themed section on Hydrogen Sulfide in Biology & Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v177.4/issuetoc., (© 2019 The British Pharmacological Society.)

CRISPR/Cas9 has become a powerful method to engineer genomes and to activate or to repress genes expression. As such, in cancer research CRISPR/Cas9 technology represents an efficient tool to dissect mechanisms of tumorigenesis and to discover novel targets for drug development. Here, we employed the CRISPR/Cas9 technology for studying the role of prostaglandin-endoperoxide synthase 2 (PTGS2) in melanoma development and progression. Melanoma is the most aggressive form of skin cancer with a median survival of less than 1 year. Although oncogene-targeted drugs and immune checkpoint inhibitors have demonstrated a significant success in improving overall survival in patients, related toxicity and emerging resistance are ongoing challenges. Gene therapy appears to be an appealing option to enhance the efficacy of currently available melanoma therapeutics leading to better patient prognosis. Several gene therapy targets have been identified and have proven to be effective against melanoma cells. Particularly, PTGS2 is frequently expressed in malignant melanomas and its expression significantly correlates with poor survival in patients. In this study we investigated on the effect of ptgs2 knockdown in B16F10 murine melanoma cells. Our results show that reduced expression of ptgs2 in melanoma cells: i ) inhibits cell proliferation, migration, and invasiveness; ii ) modulates immune response by impairing myeloid derived suppressor cell differentiation; iii ) reduces tumor development and metastasis in vivo . Collectively, these findings indicate that ptgs2 could represent an ideal gene to be targeted to improve success rates in the development of new and highly selective drugs for melanoma treatment., (Copyright © 2019 Ercolano, De Cicco, Rubino, Terrazzano, Ruggiero, Carriero, Kunderfranco and Ianaro.)

Breast cancer (BC) is the second most common cancer worldwide and the most commonly occurring malignancy in women. There is growing evidence that lifestyle factors, including diet, body weight and physical activity, may be associated with higher BC risk. However, the effect of dietary factors on BC recurrence and mortality is not clearly understood. Here, we provide an overview of the current evidence obtained from the PubMed databases in the last decade, assessing dietary patterns, as well as the consumption of specific food-stuffs/food-nutrients, in relation to BC incidence, recurrence and survival. Data from the published literature suggest that a healthy dietary pattern characterized by high intake of unrefined cereals, vegetables, fruit, nuts and olive oil, and a moderate/low consumption of saturated fatty acids and red meat, might improve overall survival after diagnosis of BC. BC patients undergoing chemotherapy and/or radiotherapy experience a variety of symptoms that worsen patient quality of life. Studies investigating nutritional interventions during BC treatment have shown that nutritional counselling and supplementation with some dietary constituents, such as EPA and/or DHA, might be useful in limiting drug-induced side effects, as well as in enhancing therapeutic efficacy. Therefore, nutritional intervention in BC patients may be considered an integral part of the multimodal therapeutic approach. However, further research utilizing dietary interventions in large clinical trials is required to definitively establish effective interventions in these patients, to improve long-term survival and quality of life.

The beneficial effects of H 2 S-release and of COXs-inhibition have been exploited in the design of novel anti-inflammatory drugs, the H 2 S-releasing non-steroidal anti-inflammatory drugs (H 2 S-NSAIDs), showing promising potential for chemoprevention in cancers. Here, we evaluated the efficacy of a new H 2 S-releasing derivative of naproxen, named naproxen-4-hydroxybenzodithioate (naproxen-HBTA), in reducing metastatic melanoma features, both in vitro and in vivo . The novel H 2 S donor has been prepared following a synthetic scheme that provided high yields and purity. In particular, we investigated the effect of naproxen-HBTA in vitro on several metastatic features of human melanoma cells such as proliferation, migration, invasion, and colonies formation and in vivo in a model of cutaneous melanoma. Cell culture studies demonstrated that naproxen-HBTA induced caspase 3-mediated apoptosis and inhibited motility, invasiveness, and focus formation. Finally, daily oral treatment with naproxen-HBTA significantly suppressed melanoma growth and progression in mice. In conclusion, by using this dual approach we propose that the COX-2 and H 2 S pathways could be regarded as novel therapeutic targets/tools to generate new treatment options based on "combination therapy" for melanoma.

Natural compounds derived from marine organisms exhibit a wide variety of biological activities. Over the last decades, a great interest has been focused on the anti-tumour role of sponges and algae that constitute the major source of these bioactive metabolites. A substantial number of chemically different structures from different species have demonstrated inhibition of tumour growth and progression by inducing apoptosis in several types of human cancer. The molecular mechanisms by which marine natural products activate apoptosis mainly include (1) a dysregulation of the mitochondrial pathway; (2) the activation of caspases; and/or (3) increase of death signals through transmembrane death receptors. This great variety of mechanisms of action may help to overcome the multitude of resistances exhibited by different tumour specimens. Therefore, products from marine organisms and their synthetic derivates might represent promising sources for new anticancer drugs, both as single agents or as co-adjuvants with other chemotherapeutics. This review will focus on some selected bioactive molecules from sponges and algae with pro-apoptotic potential in tumour cells.

Background: A strong, reciprocal crosstalk between inflammation and melanoma has rigorously been demonstrated in recent years, showing how crucial is a pro-inflammatory microenvironment to drive therapy resistance and metastasis., Purpose: We investigated on the effects of Indicaxanthin, a novel, anti-inflammatory and bioavailable phytochemical from Opuntia Ficus Indica fruits, against human melanoma both in vitro and in vivo., Study Design and Methods: The effects of indicaxanthin were evaluated against the proliferation of A375 human melanoma cell line and in a mice model of cutaneous melanoma. Cell proliferation was assessed by MTT assay, apoptosis by Annexin V-Fluorescein Isothiocyanate/Propidium Iodide staining, protein expression by western blotting, melanoma lesions were subcutaneously injected in mice with B16/F10 cells, chemokine release was quantified by ELISA., Results: Data herein presented demonstrate that indicaxanthin effectively inhibits the proliferation of the highly metastatic and invasive A375 cells as shown by growth inhibition, apoptosis induction and cell invasiveness reduction. More interestingly, in vitro data were paralleled by those in vivo showing that indicaxanthin significantly reduced tumor development when orally administered to mice. The results of our study also clarify the molecular mechanisms underlying the antiproliferative effect of indicaxanthin, individuating the inhibition of NF-κB pathway as predominant., Conclusion: In conclusion, we demonstrated that indicaxanthin represents a novel phytochemical able to significantly inhibit human melanoma cell proliferation in vitro and to impair tumor progression in vivo. When considering the resistance of melanoma to the current therapeutical approach and the very limited number of phytochemicals able to partially counteract it, our findings may be of interest to explore indicaxanthin potential in further and more complex melanoma studies in combo therapy, i.e. where different check points of melanoma development are targeted., (Copyright © 2018 Elsevier GmbH. All rights reserved.)

Malignant melanoma is one of the most leading form of skin cancer associated with a low patient survival rate. Increasing evidence revealed that microRNAs (miRNAs) play a crucial role in the occurrence and development of several form of cancer including melanoma. In this study, we aimed at investigating the expression and role of miR-143-3p in human malignant melanoma. Our results showed that the expression of miR-143-3p was lower in human melanoma cells, as well as human biopsy specimens, when compared to normal human melanocytes. Ectopic expression of miR-143-3p in human melanoma cells inhibited proliferation, migration, invasion and promoted apoptosis acting through a molecular mechanism that, at least in part, is dependent on inhibition of cyclooxygenase-2 (COX-2) gene. Collectively, these results demonstrate that miR-143-3p could represent at the same time, a new early diagnostic marker and therapeutic target acting as tumor suppressor in melanoma cancer., (Copyright © 2018. Published by Elsevier Inc.)

Chronic inflammation contributes to tumor initiation in colitis-associated colorectal cancer (CRC). Indeed, inflammatory bowel disease (IBD) patients show an increased risk of developing CRC. Cancer immune evasion is a major issue in CRC and preclinical and clinical evidence has defined a critical role for myeloid-derived suppressor cells (MDSCs) that contribute to tumor growth and progression by suppressing T-cells and modulating innate immune responses. MDSCs comprise a heterogeneous population of immature myeloid cells that can be distinct in two subtypes: CD11b + Ly6G + Ly6C low with granulocytic phenotype (G-MDSCs) and CD11b + Ly6G - Ly6C high with monocytic phenotype (M-MDSCs). Hydrogen sulfide (H 2 S) is an endogenous gaseous signaling molecule that regulates various physiological and pathophysiological functions. In particular, several studies support its anti-inflammatory activity in experimental colitis and ulcer. However, the role of the H 2 S pathway in innate immune-mediated IBD has not yet been elucidated. To better define a possible link between MDSCs and H 2 S pathway in colitis-associated CRC development, we used an innate immune-mediated IBD model induced by infection with the bacterium Helicobacter hepaticus ( Hh ), closely resembling human IBD. Here, we demonstrated an involvement of MDSCs in colitis development. A significant time-dependent increase of both G-MDSCs and M-MDSCs was observed in the colon and in the spleen of Hh -infected mice. Following, we observed that chronic oral administration of the H 2 S donor DATS reduced colon inflammation by limiting the recruitment of G-MDSCs in the colon of Hh -infected mice. Thus, we identify the metabolic pathway l-cysteine/H 2 S as a possible new player in the immunosuppressive mechanism responsible for the MDSCs-promoted colitis-associated cancer development.

Vitis vinifera cv Falanghina is an ancient grape variety of Southern Italy. A thorough phytochemical analysis of the Falanghina leaves was conducted to investigate its specialised metabolite content. Along with already known molecules, such as caftaric acid, quercetin-3-O-β-d-glucopyranoside, quercetin-3-O-β-d-glucuronide, kaempferol-3-O-β-d-glucopyranoside and kaempferol-3-O-β-d-glucuronide, a previously undescribed biflavonoid was identified. For this last compound, a moderate bioactivity against metastatic melanoma cells proliferation was discovered. This datum can be of some interest to researchers studying human melanoma. The high content in antioxidant glycosylated flavonoids supports the exploitation of grape vine leaves as an inexpensive source of natural products for the food industry and for both pharmaceutical and nutraceutical companies. Additionally, this study offers important insights into the plant physiology, thus prompting possible technological researches of genetic selection based on the vine adaptation to specific pedo-climatic environments., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Melanoma is the most common form of skin cancer. Given its high mortality, the interest in the search of preventive measures, such as dietary factors, is growing significantly. In this study we tested, in vitro and in vivo , the potential anti-cancer effect of the acetyl deacylasadisulfide (ADA), a vinyl disulfide compound, isolated and purified from asafoetida a foul-smelling oleo gum-resin of dietary and medicinal relevance. ADA markedly suppressed proliferation of human melanoma cell lines by inducing apoptosis. Moreover, treatment of melanoma cells with ADA reduced nuclear translocation and activation of NF-κB, decreased the expression of the anti-apoptotic proteins c-FLIP, XIAP, and Bcl-2 and inhibited the phosphorylation and activation of both AKT and ERK proteins, two of the most frequently deregulated pathways in melanoma. Finally, the results obtained in vitro were substantiated by the findings that ADA significantly and dose-dependently reduced lung metastatic foci formation in C57BL/6 mice. In conclusion, our findings suggest that ADA significantly inhibits melanoma progression in vivo and could represent an important lead compound for the development of new anti-metastatic agents.

Inflammation plays a key role in tumor promotion and development. Indeed, cyclooxygenase-2 (COX-2) expression is strongly associated with different types of cancer. An emerging class of compounds with significant anti-inflammatory properties is the hydrogen sulfide-releasing non-steroidal anti-inflammatory drugs (H 2 S-NSAIDs). They consist of a traditional NSAID to which an H 2 S-releasing moiety is covalently attached. We have recently demonstrated that H 2 S donors inhibit melanoma cell proliferation. In the current study, we evaluated the potential beneficial effects of a new H 2 S-releasing derivative of naproxen, ATB-346 [2-(6-methoxynapthalen-2-yl)-propionic acid 4-thiocarbamoyl phenyl ester] which inhibits COX activity but also releases H 2 S. We used cell culture and a mouse melanoma model to evaluate the effect of ATB-346 on: i) in vitro growth of human melanoma cells; ii) in vivo melanoma development in mice. Cell culture studies demonstrated that ATB-346 reduced the in vitro proliferation of human melanoma cells and this effect was associated to induction of apoptosis and inhibition of NF-κB activation. Moreover, ATB-346 had novel Akt signaling inhibitory properties. Daily oral dosing of ATB-346 (43μmol/kg) significantly reduced melanoma development in vivo. This study shows that ATB-346, a novel H 2 S-NSAID, inhibits human melanoma cell proliferation by inhibiting pro-survival pathways associated with NF-κB and Akt activation. Furthermore, oral treatment with ATB-346 inhibits melanoma growth in mice. In conclusion, the combination of inhibition of cyclooxygenase and delivery of H 2 S by ATB-346 may offer a promising alternative to existing therapies for melanoma., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The possible correlation between cyclooxygenase-2 (COX-2) expression and disease progression in melanoma is still a matter of debate. Analysis of COX-2 expression in 45 lymph node melanoma metastases demonstrates a significant correlation between the percent of expression and progression free survival (PFS). A positive COX-2 expression ≥10% (COX-2high), as opposite to a positive expression ≤9% (COX-2low), translated into a striking significant reduction of PFS of about 3 years. The reduction in PFS correlated neither with BRAFV600E nor with NRASQ61 expression in the analyzed samples. This concept was reinforced by the finding that tumour development in COX-2-/- mice was almost blunted. Similarly, inhibition of COX-2 protein expression in human melanoma cell lines, by using siRNAs technology as well as selective inhibition of COX-2 activity by celecoxib, reduced cellular proliferation and invasiveness. In conclusion we show that COX-2high is a negative prognostic factor in metastatic melanoma. Our study also clarifies that the uncertainty about the role of COX-2 in metastatic malignant melanoma, found in the current relevant literature, is probably due to the fact that a threshold in COX-2 expression has to be reached in order to impact on cancer malignancy. Our findings suggest that COX-2 expression may become an useful diagnostic tool in defining melanoma malignancy as well as argue for a possible therapeutic use of NSAID as add on therapy in selected cases., Competing Interests: No conflicts of interest to disclose.

In humans, two main metabolic enzymes synthesize hydrogen sulfide (H2 S): cystathionine γ lyase (CSE) and cystathionine β synthase (CBS). A third enzyme, 3-mercaptopyruvate sulfurtransferase (3-MST), synthesizes H2 S in the presence of the substrate 3-mercaptopyruvate (3-MP). The immunohistochemistry analysis performed on human melanoma samples demonstrated that CSE expression was highest in primary tumors, decreased in the metastatic lesions and was almost silent in non-lymph node metastases. The primary role played by CSE was confirmed by the finding that the overexpression of CSE induced spontaneous apoptosis of human melanoma cells. The same effect was achieved using different H2 S donors, the most active of which was diallyl trisulfide (DATS). The main pro-apoptotic mechanisms involved were suppression of nuclear factor-κB activity and inhibition of AKT and extracellular signal-regulated kinase pathways. A proof of concept was obtained in vivo using a murine melanoma model. In fact, either l-cysteine, the CSE substrate, or DATS inhibited tumor growth in mice. In conclusion, we have determined that the l-cysteine/CSE/H2 S pathway is involved in melanoma progression., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Oxidative stress plays an important role in the pathogenesis of inflammatory bowel disease (IBD), including Crohn's disease (CrD). High levels of Reactive Oxygen Species (ROS) induce the activation of the redox-sensitive nuclear transcription factor kappa-B (NF-κB), which in turn triggers the inflammatory mediators. Butyrate decreases pro-inflammatory cytokine expression by the lamina propria mononuclear cells in CrD patients via inhibition of NF-κB activation, but how it reduces inflammation is still unclear. We suggest that butyrate controls ROS mediated NF-κB activation and thus mucosal inflammation in intestinal epithelial cells and in CrD colonic mucosa by triggering intracellular antioxidant defense systems. Intestinal epithelial Caco-2 cells and colonic mucosa from 14 patients with CrD and 12 controls were challenged with or without lipopolysaccaride from Escherichia coli (EC-LPS) in presence or absence of butyrate for 4 and 24 h. The effects of butyrate on oxidative stress, p42/44 MAP kinase phosphorylation, p65-NF-κB activation and mucosal inflammation were investigated by real time PCR, western blot and confocal microscopy. Our results suggest that EC-LPS challenge induces a decrease in Gluthation-S-Transferase-alpha (GSTA1/A2) mRNA levels, protein expression and catalytic activity; enhanced levels of ROS induced by EC-LPS challenge mediates p65-NF-κB activation and inflammatory response in Caco-2 cells and in CrD colonic mucosa. Furthermore butyrate treatment was seen to restore GSTA1/A2 mRNA levels, protein expression and catalytic activity and to control NF-κB activation, COX-2, ICAM-1 and the release of pro-inflammatory cytokine. In conclusion, butyrate rescues the redox machinery and controls the intracellular ROS balance thus switching off EC-LPS induced inflammatory response in intestinal epithelial cells and in CrD colonic mucosa.