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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 (H2 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 H2 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 H2 S donor, diallyl trisulfide (DATS) and analysed for content of MDSCs, dendritic cells (DCs) and T cells. Effects of H2 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 H2 S donor compound, DATS, inhibited the expansion and the suppressive functions of MDSCs, suggesting a novel role for H2 S as a modulator of MDSCs in cancer. Therefore, H2 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. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. 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. [Display omitted] • Three essential oils were extracted from aerial parts of M. chamomilla by hydrodistillation. • The pharmacological mechanism behind the anti-inflammatory effect of M. chamomilla essential oils has been analyzed. • The antioxidant activity of EOs was explained throughout the activation of NRF2 signaling pathway. • EOs were able to reduce CD4+ T cell activation which are also involved in inflammatory processes. [ABSTRACT FROM AUTHOR]

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 (43 μmol/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. [ABSTRACT FROM AUTHOR]

In humans, two main metabolic enzymes synthesize hydrogen sulfide (H2S): cystathionine γ lyase ( CSE) and cystathionine β synthase ( CBS). A third enzyme, 3-mercaptopyruvate sulfurtransferase (3- MST), synthesizes H2S 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 H2S 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/H2S pathway is involved in melanoma progression. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Flavonoids have promising effects on Parkinson's Disease via certain metabolic pathways. • Flavonoids also have some epigenetic effects such as reducing apoptosis and motor deficiencies, HAT and HDAC activity. • Flavonoids can reduce pathogenic-strains and promote the beneficial-strains in gut microbiota. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: The need for new drugs in melanoma treatment is of great relevance. Indeed, current therapies for the treatment of metastatic melanoma offer a limited clinical benefit and only in recent years there has been an advancement due to the identification of new molecular targets . Hydrogen sulphide (H2S) is endogenously produced by the action of three enzymes CBS, CSE and the newly discovered 3-MST . While H2S is cytoprotective at physiological concentrations, it seems to have pro-apoptotic actions in cancer cells . However, to date there are not definitive reports on the role played by H2S in cancer development. Aim of this study was to determine the possible involvement of H2S in human melanoma. Methods: The study has been performed by using some relevant human melanoma cell lines such as A375, WM115 and SK-Mel-28. HaCat, a normal human fibroblast cell line, has been used as control. Cellular proliferation was evaluated by the MTT assay. Apoptosis was assayed by flow cytometry analysis by double staining with Annexin V and propidium iodide (PI). NF-kB/DNA-binding activity was evaluated by electrophoretic mobility shift assay. Expression of CBS, CSE, 3-MST was assayed by quantitative real time RT-PCR, expression of Bcl-2, XIAP, c-FLIP, caspase 3, PARP, IKBa and Akt/p-Akt was determined by western blotting. Levels of H2S in the supernatant and in total cellular extracts were assayed by colorimetric assay. Results: Diallyl trisulfide (DATS) is a garlic-derived polysulfide able to release H2S . Our results demonstrate that DATS greatly suppressed, in a time and concentration-dependent manner, proliferation of the three human melanoma cell lines used. The most striking effect was obtained on the A375 cell line whose proliferation was inhibited, following incubation with DATS (10–30–100μM, 72h) by 30%, 70%, and 78% respectively (p <0.001). This effect well correlated with the significant increase in H2S levels found in both supernatants and cellular lysates. Conversely, DATS up to 300 μM did not affect proliferation of HaCat. DATS-induced inhibition of A375 proliferation (10–100μM, 72h) was almost completely reversed by haemoglobin (10μM; p <0.001) a scavenger of H2S. Moreover, DATS-induced inhibition of A375 proliferation was due to the induction of apoptosis as demonstrated by FACS analysis with Annexin V/PI staining and further confirmed by the inhibition of Bcl-2, XIAP, FLIP, as well as by the cleavage and consequent activation of caspase-3 and inactivation of poly (ADP ribose) polymerase (PARP-1). Constitutive NF-kB and activated Akt expression have been described in melanoma. We also demonstrated that H2S released by DATS suppressed both constitutive NF-kB/DNA-binding activity and Akt phosphorylation suggesting that the apoptotic effect observed following exposure to H2S was consistent with the signal transduction pathways activated. Conclusion: In conclusion, we demonstrate that H2S triggers, in relevant human melanoma cell lines, an apoptotic effect. This effect, in turn, activates downstream a signal pattern that candidates H2S as a possible novel therapeutic/target or diagnostic tool. [Copyright &y& Elsevier]