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From the perspective of circular economy, it is extremely useful to recycle waste products for human health applications. Among the health-beneficial properties of bioactive phyto-compounds, grape pomace represents a precious source of bioactive molecules with potential antitumor properties. Here, we describe the effects of a Sicilian grape pomace hydroalcoholic extract (HE) in colon and breast cancer cells. The characterization of HE composition revealed the predominance of anthoxanthins and phenolic acids. HE treatment was more effective in reducing the viability of colon cancer cells, while breast cancer cells appeared more resistant. Indeed, while colon cancer cells underwent apoptosis, as shown by DNA fragmentation, caspase-3 activation, and PARP1 degradation, breast cancer cells seemed to not undergo apoptosis. To elucidate the underlying mechanisms, reactive oxygen species (ROS) were evaluated. Interestingly, ROS increased in both cell lines but, while in colon cancer, cells' ROS rapidly increased and progressively diminished over time, in breast cancer, cells' ROS increase was persistent up to 24 h. This effect was correlated with the induction of pro-survival autophagy, demonstrated by autophagosomes formation, autophagic markers increase, and protection by the antioxidant NAC. The autophagy inhibitor bafilomycin A1 significantly increased the HE effects in breast cancer cells but not in colon cancer cells. Overall, our data provide evidence that HE efficacy in tumor cells depends on a balance between ROS-mediated autophagy and apoptosis. Therefore, inhibiting pro-survival autophagy may be a tool to target those cells that appear more resistant to the effect of HE. [ABSTRACT FROM AUTHOR]

The antitumor activity of different ent-kaurane diterpenes has been extensively studied. Several investigations have demonstrated the excellent antitumor activity of synthetic derivatives of the diterpene atractyligenin. In this research, a series of new synthetic amides and their 15,19-di-oxo analogues obtained from atractyligenin by modifying the C-2, C-15, and C-19 positions were designed in order to dispose of a set of derivatives with different substitutions at the amidic nitrogen. Using different concentrations of the obtained compounds (10–300 μM) a reduction in cell viability of HCT116 colon cancer cells was observed at 48 h of treatment. All the di-oxidized compounds were more effective than their alcoholic precursors. The di-oxidized compounds had already reduced the viability of two colon cancer cells (HCT116 and Caco-2) at 24 h when used at low doses (2.5–15 μM), while they turned out to be poorly effective in differentiated Caco-2 cells, a model of polarized enterocytes. The data reported here provide evidence that di-oxidized compounds induced apoptotic cell death, as demonstrated by the appearance of condensed and fragmented DNA in treated cells, as well as the activation of caspase-3 and fragmentation of its target PARP-1. [ABSTRACT FROM AUTHOR]

Ferulago nodosa (L.) Boiss. (Apiaceae) is a species occurring in the Balkan-Tyrrhenian area being present in Crete, Greece, Albania, and probably in Macedonia. From the roots of this accession of species, not previously investigated, four coumarins, grandivittin, aegelinol benzoate, felamidin and aegelinol, and two terpenoids, (2E)-3-methyl-4-[(3-methyl-1-oxo-2-buten-1yl)oxy]-2-butenoic acid and pressafonin-A, were isolated and spectroscopically characterized. The last one was never detected in Ferulago species. The evaluation of the anti-tumor effects of F. nodosa coumarins on colon cancer HCT116 cells showed only a modest effect on reduction of tumor cell viability. For aegelinol, the reduction of colon cancer cell viability already appears with 25 µΜ, while using 50 e 100 µM doses of marmesin the residual viability amounted to 70% and 54%, respectively. This effect resulted more evident at higher doses of compounds (at 200 µM from 80% to 0%). The most effective compounds resulted coumarins lacking ester group. [ABSTRACT FROM AUTHOR]

Seseli tortuosum L. subsp. tortuosum, belonging to the Apiaceae family, is a species that grows in Europe, mainly in the Mediterranean regions. The history of its application in traditional medicine highlights its various biological properties. Trying to explore the phytochemistry and pharmacological aspects of this species, the essential oils (EOs) extracted from flowers, stems, and roots of a locally wild accession, never previously investigated, growing in Sicily, Italy, were investigated. The chemical composition of all EOs, obtained by the hydrodistillation method, was evaluated by GC-MS. The most abundant class of all investigated samples was that of monoterpene hydrocarbons (79.98–91.21%) with p-cymene, α-pinene, β-pinene, and β-ocimene as major compounds. These EOs, and their main components, were tested for their possible anticancer activity. Obtained data provided evidence that among the different EOs tested, at the dose of 100 μg/mL, those extracted from stems and roots were particularly effective, already at 24 h of treatment, in reducing the cell viability of 42% and 95%, respectively, in HCT116 colon cancer cell line. These EOs also exerted a remarkable cytotoxic effect that was accompanied by morphological changes represented by cell shrinkage as well as a reduction in residual cell population. Differently, modest effects were found when EOs extracted from flowers were tested in the same experimental conditions. The evaluation of the phytocompounds mainly represented in the EOs extracted from different parts of the plant and tested in a range of concentrations between 20 and 200 μg/mL, revealed that α-pinene, β-pinene, and p-cymene exerted only modest effects on cell viability. Differently, a remarkable effect was found when β-ocimene, the most abundant phytocomponent in EOs from roots, was tested on colon cancer cells. This phytocompound, among those identified in EOs from Seseli tortuosum L. subsp. tortuosum, was found to be the most effective in reducing colon cancer cell viability with IC50 = 64.52 μg/mL at 24 h of treatment. All together, these data suggest that β-ocimene could be responsible for the effects observed in colon cancer cells. [ABSTRACT FROM AUTHOR]

This document is a special issue of the International Journal of Molecular Sciences titled "Inflammatory Signaling Pathways Involved in Gastrointestinal Diseases." It contains six papers, including two research articles and four reviews, that explore the role of inflammation in gastrointestinal diseases and potential therapeutic strategies. The papers discuss topics such as chronic inflammation in Inflammatory Bowel Disease (IBD), the role of heat shock proteins and histamine in IBD, the use of polyphenols as anti-inflammatory agents, the potential of miR-369-3p as a therapeutic approach for IBD, the relationship between gut disorders and immune system deregulation, and the pathogenesis of Barrett's esophagus. The authors express gratitude to the contributors and declare no conflicts of interest. [Extracted from the article]

Origanum vulgare L. is an aromatic plant that exerts antibacterial, antioxidant, anti-inflammatory, and antitumor activities, mainly due to its essential oil (EO) content. In this study, we investigated the possible mechanism underlying the in vitro antitumor activity of EO extracted by hydrodistillation of dried flowers and leaves of Origanum vulgare L. grown in Sicily (Italy) in MDA-MB-231 and MCF-7 breast cancer cell lines. Gas chromatography–mass spectrometry analysis of Oregano essential oil (OEO) composition highlighted the presence of twenty-six major phytocompounds, such as p-cymene, γ-terpinene, and thymoquinone p-acetanisole. OEO possesses strong antioxidant capacity, as demonstrated by the DPPH test. Our studies provided evidence that OEO reduces the viability of both MCF-7 and MDA-MB-231 cells. The cytotoxic effect of OEO on breast cancer cells was partially counteracted by the addition of z-VAD-fmk, a general caspase inhibitor. Caspases and mitochondrial dysfunction appeared to be involved in the OEO-induced death mechanism. Western blotting analysis showed that OEO-induced activation of pro-caspases-9 and -3 and fragmentation of PARP decreased the levels of Bcl-2 and Bcl-xL while increasing those of Bax and VDAC. In addition, fluorescence microscopy and cytofluorimetric analysis showed that OEO induces a loss of mitochondrial membrane potential in both cell lines. Furthermore, we tested the effects of p-cymene, γ-terpinene, thymoquinone, and p-acetanisole, which are the main components of OEO. Our findings highlighted that the effect of OEO on MDA-MB-231 and MCF-7 cells appears to be mainly due to the combination of different constituents of OEO, providing evidence of the potential use of OEO for breast cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Laryngeal squamous cell carcinoma is a prevalent cancer associated with poor prognosis in advanced stages. Despite advancements in diagnostic tools (e.g., narrow-band imaging), there have been minimal improvements in therapeutic approaches. The potential new frontier lies in the realm of biomarkers. This review aims to outline the current understanding of biomarkers in laryngeal cancer. Specifically, it concentrates on potential biomarkers, including heat shock proteins, metallothioneins, nuclear factor erythroid 2-related factor 2, micro ribonucleic acids, heme oxygenase, and cyclooxygenase-2. This review provides a survey of the existing literature on their role in laryngeal cancer. It also underscores the scarcity of the literature on this subject, highlighting the significant role of biomarkers in formulating more precise therapeutic strategies for individual patients. Laryngeal squamous cell carcinoma (LSCC) is the second most common cancer among head and neck cancers. Despite a lower incidence of laryngeal carcinoma, new diagnostic techniques, and more targeted therapies, the overall survival has not changed significantly in the last decades, leading to a negative prognosis in advanced stages. Recently, several studies have focused on the identification of biomarkers that may play a critical role in the pathogenesis of LSCC. Reviewing the literature on the main databases, this study aims to investigate the role of some biomarkers in LSCC that are correlated with oxidative stress and inflammation: heat shock proteins; metallothioneins; nuclear factor erythroid 2-related factor 2; heme oxygenase; cyclooxygenase-2; and micro ribonucleic acids. This review shows that biomarker expression depends on the type, grade of differentiation, stage, and site of carcinoma. In addition, the role of these biomarkers in LSCC is still little-known and little-studied. However, the study of biomarker expression and the detection of a possible correlation with patients' epidemiological, clinicopathological, and therapeutics data may lead to better awareness and knowledge of the tumor, to the identification of the best therapeutic strategy, and the most proper follow-up protocol tailored for each patient. In conclusion, the achievement of these goals may improve the prognosis of LSCC patients. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease (IBD) is a chronic and progressive inflammatory disorder affecting the gastrointestinal tract (GT) caused by a wide range of genetic, microbial, and environmental factors. IBD is characterized by chronic inflammation and decreased gut microbial diversity, dysbiosis, with a lower number of beneficial bacteria and a concomitant increase in pathogenic species. It is well known that dysbiosis is closely related to the induction of inflammation and oxidative stress, the latter caused by an imbalance between reactive oxygen species (ROS) production and cellular antioxidant capacity, leading to cellular ROS accumulation. ROS are responsible for intestinal epithelium oxidative damage and the increased intestinal permeability found in IBD patients, and their reduction could represent a potential therapeutic strategy to limit IBD progression and alleviate its symptoms. Recent evidence has highlighted that dietary polyphenols, the natural antioxidants, can maintain redox equilibrium in the GT, preventing gut dysbiosis, intestinal epithelium damage, and radical inflammatory responses. Here, we suggest that the relatively new foodomics approaches, together with new technologies for promoting the antioxidative properties of dietary polyphenols, including novel delivery systems, chemical modifications, and combination strategies, may provide critical insights to determine the clinical value of polyphenols for IBD therapy and a comprehensive perspective for implementing natural antioxidants as potential IBD candidate treatment. [ABSTRACT FROM AUTHOR]

Triple-Negative Breast Cancer (TNBC) is a particularly aggressive subtype among breast cancers (BCs), characterized by anoikis resistance, high invasiveness, and metastatic potential as well as Epithelial–Mesenchymal Transition (EMT) and stemness features. In the last few years, our research focused on the function of MCL1, an antiapoptotic protein frequently deregulated in TNBC. Here, we demonstrate that MCL1 inhibition by A-1210477, a specific BH3-mimetic, promotes anoikis/apoptosis in the MDA-MB-231 cell line, as shown via an increase in proapoptotic markers and caspase activation. Our evidence also shows A-1210477 effects on Focal Adhesions (FAs) impairing the integrin trim and survival signaling pathways, such as FAK, AKT, ERK, NF-κB, and GSK3β-inducing anoikis, thus suggesting a putative role of MCL1 in regulation of FA dynamics. Interestingly, in accordance with these results, we observed a reduction in migratory and invasiveness capabilities as confirmed by a decrease in metalloproteinases (MMPs) levels following A-1210477 treatment. Moreover, MCL1 inhibition promotes a reduction in EMT characteristics as demonstrated by the downregulation of Vimentin, MUC1, DNMT1, and a surprising re-expression of E-Cadherin, suggesting a possible mesenchymal-like phenotype reversion. In addition, we also observed the downregulation of stemness makers such as OCT3/4, SOX2, NANOG, as well as CD133, EpCAM, and CD49f. Our findings support the idea that MCL1 inhibition in MDA-MB-231 could be crucial to reduce anoikis resistance, aggressiveness, and metastatic potential and to minimize EMT and stemness features that distinguish TNBC. [ABSTRACT FROM AUTHOR]

10.3390/ijms23179867 27 DiNicolantonio J.J., O'Keefe J.H. Good Fats versus Bad Fats: A Comparison of Fatty Acids in the Promotion of Insulin Resistance, Inflammation, and Obesity. Li et al. showed that 4-ME treatment attenuated adipocyte hypertrophy, macrophage infiltration, hypoxia and fibrosis in epididymal adipose tissue in HFD-fed mice, thus improving the adipose tissue microenvironment. As a consequence, hypoxia of fat cells increases glucose consumption, promoting the development of adipocyte insulin resistance and adipose tissue fibrosis [[14]]. [Extracted from the article]

Oncogenic BRAF mutations have been widely described in melanomas and promote tumour progression and chemoresistance. We previously provided evidence that the HDAC inhibitor ITF2357 (Givinostat) targets oncogenic BRAF in SK-MEL-28 and A375 melanoma cells. Here, we show that oncogenic BRAF localises to the nucleus of these cells, and the compound decreases BRAF levels in both the nuclear and cytosolic compartments. Although mutations in the tumour suppressor p53 gene are not equally frequent in melanomas compared to BRAF, the functional impairment of the p53 pathway may also contribute to melanoma development and aggressiveness. To understand whether oncogenic BRAF and p53 may cooperate, a possible interplay was considered in the two cell lines displaying a different p53 status, being p53 mutated into an oncogenic form in SK-MEL-28 and wild-type in A375 cells. Immunoprecipitation revealed that BRAF seems to preferentially interact with oncogenic p53. Interestingly, ITF2357 not only reduced BRAF levels but also oncogenic p53 levels in SK-MEL-28 cells. ITF2357 also targeted BRAF in A375 cells but not wild-type p53, which increased, most likely favouring apoptosis. Silencing experiments confirmed that the response to ITF2357 in BRAF-mutated cells depends on p53 status, thus providing a rationale for melanoma-targeted therapy. [ABSTRACT FROM AUTHOR]

Methyl gallate (MG), which is a gallotannin widely found in plants, is a polyphenol used in traditional Chinese phytotherapy to alleviate several cancer symptoms. Our studies provided evidence that MG is capable of reducing the viability of HCT116 colon cancer cells, while it was found to be ineffective on differentiated Caco-2 cells, which is a model of polarized colon cells. In the first phase of treatment, MG promoted both early ROS generation and endoplasmic reticulum (ER) stress, sustained by elevated PERK, Grp78 and CHOP expression levels, as well as an upregulation in intracellular calcium content. Such events were accompanied by an autophagic process (16–24 h), where prolonging the time (48 h) of MG exposure led to cellular homeostasis collapse and apoptotic cell death with DNA fragmentation and p53 and γH2Ax activation. Our data demonstrated that a crucial role in the MG-induced mechanism is played by p53. Its level, which increased precociously (4 h) in MG-treated cells, was tightly intertwined with oxidative injury. Indeed, the addition of N-acetylcysteine (NAC), which is a ROS scavenger, counteracted the p53 increase, as well as the MG effect on cell viability. Moreover, MG promoted p53 accumulation into the nucleus and its inhibition by pifithrin-α (PFT-α), which is a negative modulator of p53 transcriptional activity, enhanced autophagy, increased the LC3-II level and inhibited apoptotic cell death. These findings provide new clues to the potential action of MG as a possible anti-tumor phytomolecule for colon cancer treatment. [ABSTRACT FROM AUTHOR]

A diet rich in saturated fatty acids (FAs) has been correlated with metabolic dysfunction and ROS increase in the adipose tissue of obese subjects. Thus, reducing hypertrophy and oxidative stress in adipose tissue can represent a strategy to counteract obesity and obesity-related diseases. In this context, the present study showed how the peel and seed extracts of mango (Mangifera indica L.) reduced lipotoxicity induced by high doses of sodium palmitate (PA) in differentiated 3T3-L1 adipocytes. Mango peel (MPE) and mango seed (MSE) extracts significantly lowered PA-induced fat accumulation by reducing lipid droplet (LDs) and triacylglycerol (TAGs) content in adipocytes. We showed that MPE and MSE activated hormone-sensitive lipase, the key enzyme of TAG degradation. In addition, mango extracts down-regulated the adipogenic transcription factor PPARγ as well as activated AMPK with the consequent inhibition of acetyl-CoA-carboxylase (ACC). Notably, PA increased endoplasmic reticulum (ER) stress markers GRP78, PERK and CHOP, as well as enhanced the reactive oxygen species (ROS) content in adipocytes. These effects were accompanied by a reduction in cell viability and the induction of apoptosis. Interestingly, MPE and MSE counteracted PA-induced lipotoxicity by reducing ER stress markers and ROS production. In addition, MPE and MSE increased the level of the anti-oxidant transcription factor Nrf2 and its targets MnSOD and HO-1. Collectively, these results suggest that the intake of mango extract-enriched foods in association with a correct lifestyle could exert beneficial effects to counteract obesity. [ABSTRACT FROM AUTHOR]

Artemisia arborescens (Vaill.) L. is a perennial shrubby plant growing along the coastal strips of the Mediterranean region. It is used in traditional medicine. Its essential oil and solvent extracts exhibit a very interesting chemotherapeutic potential, which makes this plant useful in maintaining human health. The goal of this study was to determine the phytochemical composition of the petroleum ether and methanol extracts, as well as to evaluate anticancer activities and antimicrobial and biofilm formation reduction. Thirty-nine phytochemical compounds in negative ion mode and 25 in positive ion mode were identified by HPLC-ESI-QTOF-MS. All four extracts reduced the viability of human MDA-MB231 and HCT116 cancer cells suggesting a similar cytotoxic efficacy of the different extracts in MDA-MB231 and more pronounced antiproliferative effects on HCT116 cells treated with HPEE and CPEE. Antimicrobial activity was exhibited by the hot petroleum ether extract against all tested bacteria (MIC 0.15–2.5 mg/mL), except for S. agalactiae. Both methanol extracts showed activity against C. albicans with a MIC value of 2.5 mg/mL, and a lack of antibacterial activity. To whom concern the anti-biofilm activity, hot methanol extract shows the highest activity in inhibiting biofilm formation among all extract. [ABSTRACT FROM AUTHOR]

Helianthemum lippii is a perennial shrubby plant growing in the sandy environments of Italy, Mediterranean countries of North Africa and Middle East. H. lippii is used in traditional medicine but there are very few reports referring to the phytochemical characterization, the ethnopharmacology, and the biological activity of H. lippii. The goal of this study was to determine the phytochemical composition of different H. lippii extracts, cold (CME) and hot (HME) methanol, cold (CPEE) and hot (HPEE) petroleum ether, as well as to evaluate their anticancer and antimicrobial activities and biofilm formation reduction. Fifty-fours phytocompounds have been determined by HPLC-UV-ESI-QTOF-MS analysis. All the four extracts reduced the viability of human MDA-MB231 and HCT116 cells, being cold and hot methanol extracts the most effective. The antimicrobial activity against S. aureus, P. aeruginosa, E. faecalis, E. coli, C. albicans was also evaluated. Data showed the greater susceptibility of S. aureus to hot methanolic extract. Concerning antifungal activity, C. albicans resulted more susceptible to petroleum ether. Moreover, some of the samples exhibited a good antibiofilm activity both on immature and on mature biofilms. The four extracts showed interesting antimicrobial and cytotoxic activities and can be considered good candidates for new therapeutic applications [ABSTRACT FROM AUTHOR]

Histone deacetylase inhibitors (HDACI) are epigenetic compounds that have been widely considered very promising antitumor agents. Here, we focus on the effects of the pan-HDAC inhibitor ITF2357 (Givinostat) in comparison with SAHA (Vorinostat) in melanoma cells bearing BRAF V600E oncogenic mutation. Our results indicate both ITF2357 and SAHA dose-dependently reduce the viability of BRAF-mutated SK-MEL-28 and A375 melanoma cells. The comparison of IC50 values revealed that ITF2357 was much more effective than SAHA. Interestingly, both inhibitors markedly decreased oncogenic BRAF protein expression levels, ITF2357 being the most effective compound. Moreover, the BRAF decrease induced by ITF2357 was accompanied by a decrease in the level of phospho-ERK1/2. The inhibitor of upstream MEK activity, U0126, reduced ERK1/2 phosphorylation and dramatically potentiated the antitumor effect of ITF2357, exacerbating the reduction in the BRAF level. ITF2357 stimulated an early pro-survival autophagic response, which was followed by apoptosis, as indicated by apoptotic markers evaluation and the protective effects exerted by the pan-caspase inhibitor z-VADfmk. Overall, our data indicate for the first time that ITF2357 targets oncogenic BRAF in melanoma cells and induces a switch from autophagy to classic apoptosis, thus representing a possible candidate in melanoma targeted therapy. [ABSTRACT FROM AUTHOR]

Programmed cell death is fundamental for multicellular organisms either in animal or plant kingdom. Classic apoptosis, which represents the best studied form of cell death, is dependent on caspase protease activity in animals. These proteases are not present in plants, where caspase-like activities, including metacaspases, are involved in the execution of plant cell death. Beyond apoptosis, various non-apoptotic forms of cell death also exist, including autophagy, necroptosis, pyroptosis, and ferroptosis. These types of cell death can be activated independently of apoptosis and sometimes occur when apoptosis is inhibited. Non-apoptotic forms of cell death are best characterized in animals, whereas, in plants, the literature is less extensive, but the molecular executioners of plant cell death are becoming clearer. The aim of this review is to describe different types of cell death and the mechanisms involved in animals and plants, highlighting similarities and differences in the two kingdoms. Moreover, implications of cell death pathways in cancer are discussed. [ABSTRACT FROM AUTHOR]

Litchi is a tasty fruit that is commercially grown for food consumption and nutritional benefits in various parts of the world. Due to its biological activities, the fruit is becoming increasingly known and deserves attention not only for its edible part, the pulp, but also for its peel and seed that contain beneficial substances with antioxidant, cancer preventive, antimicrobial, and anti-inflammatory functions. Although literature demonstrates the biological activity of Litchi components in reducing tumor cell viability in in vitro or in vivo models, data about the biochemical mechanisms responsible for these effects are quite fragmentary. This review specifically describes, in a comprehensive analysis, the antitumor properties of the different parts of Litchi and highlights the main biochemical mechanisms involved. [ABSTRACT FROM AUTHOR]

Historically, Mangifera indica L. cultivations have been widely planted in tropical areas of India, Africa, Asia, and Central America. However, at least 20 years ago its spreading allowed the development of some cultivars in Sicily, an island to the south of Italy, where the favourable subtropical climate and adapted soils represent the perfect field to create new sources of production for the Sicilian agricultural supply chain. Currently, cultivations of Kensington Pride, Keitt, Glenn, Maya, and Tommy Atkins varieties are active in Sicily and their products meet the requirements of local and European markets. Mango plants produce fleshy stone fruits rich in phytochemicals with an undisputed nutritional value for its high content of polyphenolics and vitamins. This review provides an overview of the antioxidant, anti-inflammatory, and anticancer properties of mango, a fruit that should be included in everyone's diet for its multifaceted biochemical actions and health-enhancing properties. [ABSTRACT FROM AUTHOR]

The sesquiterpene lactone Parthenolide (PN) exerted a cytotoxic effect on MDA-MB231 cells, a triple-negative breast cancer (TNBC) cell line, but its effectiveness was scarce when employed at low doses. This represents an obstacle for a therapeutic utilization of PN. In order to overcome this difficulty we associated to PN the suberoylanilide hydroxamic acid (SAHA), an histone deacetylase inhibitor. Our results show that SAHA synergistically sensitized MDA-MB231 cells to the cytotoxic effect of PN. It is noteworthy that treatment with PN alone stimulated the survival pathway Akt/mTOR and the consequent nuclear translocation of Nrf2, while treatment with SAHA alone induced autophagic activity. However, when the cells were treated with SAHA/PN combination, SAHA suppressed PN effect on Akt/mTOR/Nrf2 pathway, while PN reduced the prosurvival autophagic activity of SAHA. In addition SAHA/PN combination induced GSH depletion, fall in Δψm, release of cytochrome c, activation of caspase 3 and apoptosis. Finally we demonstrated that combined treatment maintained both hyperacetylation of histones H3 and H4 induced by SAHA and down-regulation of DNMT1 expression induced by PN. Inhibition of the DNA-binding activity of NF-kB, which is determined by PN, was also observed after combined treatment. In conclusion, combination of PN to SAHA inhibits the cytoprotective responses induced by the single compounds, but does not alter the mechanisms leading to the cytotoxic effects. Taken together our results suggest that this combination could be a candidate for TNBC therapy. J. Cell. Physiol. 230: 1276-1289, 2015. © 2014 Wiley Periodicals, Inc., A Wiley Company [ABSTRACT FROM AUTHOR]

At present, the growing spread of tumor cases worldwide renders the research of new promising and selective anticancer drugs urgent. The biological action of extracts of medicinal plants or their essential oils (EOs) is an emerging field of interest, since they could comprise a rich source of phytochemicals that can prove promising. In the present study, the biological activity and mechanism of action of the EO of Foeniculum vulgare subsp. piperitum fruits (FVPEO) were investigated using MTT assays, morphological analyses and western blotting in MDA-MB231 cells, a triple-negative breast cancer cell line. The findings revealed that FVPEO could exert strong anticancer effects, causing a dose-dependent inhibition of breast cancer MDA-MB231 cell growth, accompanied with DNA condensation and fragmentation. The cytotoxic effect of FVPEO was counteracted by the addition of the antioxidant N-acetylcysteine and was associated with a marked increase in reactive oxygen species and stress-related proteins; such as manganese superoxide dismutase, c-Jun, phospho-c-Jun N-terminal kinase and nuclear factor E2-related factor 2, and the latter's transcriptional targets, Heme oxygenase-1 and NAD(P)H quinone oxidoreductase 1 (NQO1). As evidenced by the activation of caspase-3 and fragmentation of poly(ADP-ribose) polymerase-1, which are typical apoptosis markers, FVPEO promoted apoptotic cell death accompanied with an increase in phosphorylated H2A histone family member X and the activation of the NQO1/p53 axis. In combination, the present experiments provided evidence that FVPEO could represent a reservoir of biologically active compounds suitable for both cancer prevention and treatment. [ABSTRACT FROM AUTHOR]

For a long time, adipose tissue has been considered an inert tissue involved in fat accumulation. Thus, the knowledge of the underlying pathophysiological mechanisms of obesity and the identification of new compounds with anti-obesity effects represents a strategy for reducing obesity and its related comorbidities. 10.3389/fphar.2015.00199 28 Ma J., Wang Y., Ding J., Zhang S., Yang Y., Sun C. SAHA Induces White Fat Browning and Rectifies Metabolic Dysfunctions via Activation of ZFPs. Indeed, the identification of targeted drugs regulating signaling and epigenetic status in adipogenesis could shed light on the treatment of obesity or related metabolic diseases through modulating adipogenesis [[26]]. [Extracted from the article]

Due to its chemical properties and multiple molecular effects on different tumor cell types, the sesquiterpene lactone parthenolide (PN) can be considered an effective drug with significant potential in cancer therapy. PN has been shown to induce either classic apoptosis or alternative caspase-independent forms of cell death in many tumor models. The therapeutical potential of PN has been increased by chemical design and synthesis of more soluble analogues including dimethylaminoparthenolide (DMAPT). This review focuses on the molecular mechanisms of both PN and analogues action in tumor models, highlighting their effects on gene expression, signal transduction and execution of different types of cell death. Recent findings indicate that these compounds not only inhibit prosurvival transcriptional factors such as NF-κB and STATs but can also determine the activation of specific death pathways, increasing intracellular reactive oxygen species (ROS) production and modifications of Bcl-2 family members. An intriguing property of these compounds is its specific targeting of cancer stem cells. The unusual actions of PN and its analogues make these agents good candidates for molecular targeted cancer therapy. [ABSTRACT FROM AUTHOR]

Several studies highlighted the beneficial value of natural compounds in the prevention and treatment of obesity. Here, we investigated the anti-obesity effects of extracts of peel and seed of mango (Mangifera indica L.) cultivated in Sicily (Italy) in 3T3-L1 cells. Mango Peel (MPE) and Mango Seed (MSE) extracts at a 100 µg/mL concentration significantly reduced lipid accumulation and triacylglycerol contents during 3T3-L1 adipocyte differentiation without toxicity. HPLC-ESI-MS analysis showed that both the extracts contain some polyphenolic compounds that can account for the observed biological effects. The anti-adipogenic effect of MPE and MSE was the result of down-regulation of the key adipogenic transcription factor PPARγ and its downstream targets FABP4/aP2, GLUT4 and Adipsin, as well SREBP-1c, a transcription factor which promotes lipogenesis. In addition, both MPE and MSE significantly activated AMPK with the consequent inhibition of Acetyl-CoA-carboxylase (ACC) and up-regulated PPARα. The addition of compound C, a specific AMPK inhibitor, reduced the effects of MPE and MSE on AMPK and ACC phosphorylation, suggesting a role of AMPK in mediating MPE and MSE anti-lipogenic effects. Notably, MPE and MSE possess an elevated radical scavenging activity, as demonstrated by DPPH radical scavenging assay, and reduced ROS content produced during adipocyte differentiation. This last effect could be a consequence of the increase in the antioxidant factors Nrf2, MnSOD and HO-1. In conclusion, MPE and MSE possesses both anti-adipogenic and antioxidant potential, thus suggesting that the bio-waste products of mango are promising anti-obesity natural compounds. [ABSTRACT FROM AUTHOR]

The mechanism of the cytotoxic effect exerted by parthenolide on tumor cells is not clearly defined today. This article shows that parthenolide stimulates in human osteosarcoma MG63 and melanoma SK-MEL-28 cells a mechanism of cell death, which is not prevented by z-VAD-fmk and other caspase inhibitors. In particular treatment with parthenolide rapidly stimulated (1-2 h) reactive oxygen species (ROS) generation by inducing activation of extracellular signal-regulated kinase 1/2 (ERK 1/2) and NADPH oxidase. This event caused depletion of thiol groups and glutathione, NF-κB inhibition, c-Jun N-terminal kinase (JNK) activation, cell detachment from the matrix, and cellular shrinkage. The increase of ROS generation together with the mitochondrial accumulation of Ca2+ also favored dissipation of Δψm, which seemed primarily determined by permeability transition pore opening, since Δψm loss was partially prevented by the inhibitor cyclosporin A. Staining with Hoechst 33342 revealed in most cells, at 3-5 h of treatment, chromatin condensation, and fragmentation, while only few cells were propidium iodide (PI)-positive. In addition, at this stage apoptosis inducing factor (AIF) translocated to the nucleus and co-localized with areas of condensed chromatin. Prolonging the treatment (5-15 h) ATP content declined while PI-positive cells strongly augmented, denouncing the increase of necrotic effects. All these effects were prevented by N-acetylcysteine, while caspase inhibitors were ineffective. We suggest that AIF exerts a crucial role in parthenolide action. In accordance, down-regulation of AIF markedly inhibited parthenolide effect on the production of cells with apoptotic or necrotic signs. Taken together our results demonstrate that parthenolide causes in the two cell lines a caspase-independent cell death, which is mediated by AIF. J. Cell. Physiol. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

This article shows that HepG2, Hep3B, and SK-Hep1 cells, three lines of human hepatocellular carcinoma (HCC) cells, are resistant to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Parthenolide, a sesquiterpene lactone found in European feverfew, has been shown to exert both anti-inflammatory and anti-cancer activities. This article demonstrates that co-treatment with parthenolide and TRAIL-induced apoptosis with synergistic interactions in the three lines of HCC cells. In order to explain these effects we ascertained that parthenolide increased either at protein or mRNA level the total content of death receptors TRAIL-R1 and -R2 as well as their surface expression. These effects were found in the three cell lines in the case of TRAIL-R2, while for TRAIL-R1 they were observed in HepG2 and SK-Hep1 cells, but not in Hep3B cells. We suggest that the effects of parthenolide on death receptors depend on the decrease in the level of phosphorylated and active forms of STAT proteins, an event which could be a consequence of the inhibitory effect exerted by parthenolide on the activation of JAK proteins. In agreement with this hypothesis treatment with STAT3 siRNA increased in HCC cells the effect of parthenolide on the expression of death receptors. Sensitization by parthenolide to TRAIL stimulated in the three cell lines the extrinsic mechanism of apoptosis with the activation of both caspases 8 and 3, whereas mitochondria were not involved in the process. Our results suggest that co-treatment with parthenolide and TRAIL could represent a new important therapeutic strategy for hepatic tumors. J. Cell. Physiol. 226: 1632-1641, 2011. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Abstract: This paper shows that the histone deacetylase inhibitor SAHA sensitised at sub-toxic doses human hepatocellular carcinoma cells (HepG2, Hep3B and SK-Hep1) to TRAIL-induced apoptosis, while it was ineffective in primary human hepatocytes (PHHs). In particular in HCC cells SAHA increased the expression of death receptor 5 (DR5) and caused a decrement of c-Flip. These two modifications provoked in the presence of TRAIL the rapid production of TRAIL-DISC and the activation of caspase-8. Consequently SAHA/TRAIL combination induced many apoptotic events, such as a cleavage of Bid into tBid, dissipation of mitochondrial membrane potential, activation of caspase-3 with the consequent cleavage of both NF-kB and Akt. The decrease in NF-kB level seemed to be responsible for the reduction in the content of IAP family antiapoptotic proteins while the decrease in Akt level caused a reduction in phospho-Bad. These events led to the activation of caspase-9, which contributed to the strong apoptotic activity of TRAIL. Sensitisation of human hepatocellular carcinoma cells to TRAIL-induced apoptosis by SAHA may suggest new strategies for the treatment of liver tumours. [Copyright &y& Elsevier]

Obesity is a complex disease caused by an excessive amount of body fat. Obesity is a medical problem and represents an important risk factor for the development of serious diseases such as insulin resistance, type 2 diabetes, cardiovascular disease, and some types of cancer. Not to be overlooked are the psychological issues that, in obese subjects, turn into very serious pathologies, such as depression, phobias, anxiety, and lack of self-esteem. In addition to modifying one's lifestyle, the reduction of body mass can be promoted by different natural compounds such as essential oils (EOs). EOs are mixtures of aromatic substances produced by many plants, particularly in medicinal and aromatic ones. They are odorous and volatile and contain a mixture of terpenes, alcohols, aldehydes, ketones, and esters. Thanks to the characteristics of the various chemical components present in them, EOs are used in the food, cosmetic, and pharmaceutical fields. Indeed, it has been shown that EOs possess great antibiotic, anti-inflammatory, and antitumor powers. Emerging results also demonstrate the anti-obesity effects of EOs. We have examined the main data obtained in experimental studies and, in this review, we summarize the effect of EOs in obesity and obesity-related metabolic diseases. [ABSTRACT FROM AUTHOR]

This paper studies the effects caused in human retinoblastoma Y79 cells by treatment with combinations of sodium butyrate, the inhibitor of topoisomerase I camptothecin and the inhibitor of 26S proteasome MG132. The combination of sodium butyrate and camptothecin resulted in a strong synergistic cytotoxicity, as revealed by combination indices of 0.77 and 0.52 calculated at IC50 and IC75. Synergistic interactions were also demonstrated for combinations of sodium butyrate and MG132, camptothecin and MG132 and for a combination of all three compounds. The cytotoxic effects observed after the combined treatments can be considered a consequence of apoptosis, as suggested by the appearance of morphological signals of apoptosis and by the activation of caspase-3 with degradation of poly-ADP ribose polymerase and lamin B. Treatment of Y79 cells with sodium butyrate alone lowered the levels of p53, E2F-1 and Bcl-2. The addition of MG132 to sodium butyrate counteracted the effect on p53 only, while the addition of camptothecin to sodium butyrate counteracted the effect on both p53 and E2F-1. The treatment of Y79 cells with the triple combination increased the level of p53, decreased that of Bcl-2, while the level of E2F-1 was not modified. We suggest that the effects exerted on the levels of these regulatory proteins can explain the synergistic interactions demonstrated between sodium butyrate, camptothecin and MG132. Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a well-known transcription factor best recognised as one of the main regulators of the oxidative stress response. Beyond playing a crucial role in cell defence by transactivating cytoprotective genes encoding antioxidant and detoxifying enzymes, Nrf2 is also implicated in a wide network regulating anti-inflammatory response and metabolic reprogramming. Such a broad spectrum of actions renders the factor a key regulator of cell fate and a strategic player in the control of cell transformation and response to viral infections. The Nrf2 protective roles in normal cells account for its anti-tumour and anti-viral functions. However, Nrf2 overstimulation often occurs in tumour cells and a complex correlation of Nrf2 with cancer initiation and progression has been widely described. Therefore, if on one hand, Nrf2 has a dual role in cancer, on the other hand, the factor seems to display a univocal function in preventing inflammation and cytokine storm that occur under viral infections, specifically in coronavirus disease 19 (COVID-19). In such a variegate context, the present review aims to dissect the roles of Nrf2 in both cancer and COVID-19, two widespread diseases that represent a cause of major concern today. In particular, the review describes the molecular aspects of Nrf2 signalling in both pathological situations and the most recent findings about the advantages of Nrf2 inhibition or activation as possible strategies for cancer and COVID-19 treatment respectively. [ABSTRACT FROM AUTHOR]

Today, an improved understanding of cancer cell response to cellular stress has become more necessary. Indeed, targeting the intracellular pro-oxidant/antioxidant balance triggering the tumor commitment to cell demise could represent an advantageous strategy to develop cancer-tailored therapies. In this scenario, the present study shows how the peel extract of mango—a tropical fruit rich in phytochemicals with nutraceutical properties—can affect the cell viability of three colon cancer cell lines (HT29, Caco-2 and HCT116), inducing an imbalance of cellular redox responses. By using hydro-alcoholic mango peel extract (MPE), we observed a consistent decline in thiol group content, which was accompanied by upregulation of MnSOD—a mitochondrial scavenger enzyme that modulates the cellular response against oxidative damage. Such an effect was the consequence of an early production of mitochondrial superoxide anions that appeared after just 30 min of exposure of colon cancer cells to MPE. The effect was accompanied by mitochondrial injury, consisting of the dissipation of mitochondrial membrane potential and a decrease in the level of proteins localized in the mitochondrial membrane—such as voltage-dependent anion-selective channel (VDAC1), mitofilin, and some members of Bcl-2 family proteins (Mcl-1, Bcl-2 and Bcl-XL)—with the mitochondrial release of apoptogenic factors (cytochrome C and AIF). The analysis of the cytotoxic effects exerted by the different constituents of MPE (gallic acid, mangiferin, citric acid, quinic acid, pentagalloyl glucose, and methyl gallate) allowed us to identify those phytochemicals responsible for the observed anticancer effects, sustaining their future employment as chemopreventive or therapeutic agents. [ABSTRACT FROM AUTHOR]

C2-ceramide, a cell-permeable analogue of ceramide, induced significant, dose- and time-dependent death in human retinoblastoma Y79 cells. Dying cells strongly displayed the morphology of apoptosis as characterized by microscopic evidence of cell shrinkage, membrane blebbing, nuclear and chromatin condensation and degeneration of the nucleus into membrane-bound apoptotic bodies. Upon induction of apoptosis Y79 cells evidence early phosphatidylserine externalization, as shown by annexin V-FITC. Apoptosis was also assessed by monitoring changes in cell granularity by staining with the combined fluorescent dyes acridine orange and ethidium bromide. C2-ceramide induced these morphological changes without a concomitant production of oligonucleosomal fragments responsible for the DNA ladder and without changes in p53 protein level. Apoptosis was accompanied by accumulation of a modified Bcl-2 protein with a slower-mobility form, and by proteolytic cleavage of PARP. The effect seemed to be specific for C2-ceramide, as C2-dihydroceramide, or other amphiphilic lipid analogues, or products of ceramide hydrolysis were ineffective. The effect also depended on mRNA and protein synthesis as it was markedly inhibited by actinomycin D and cycloheximide. Sphingomyelinase and interleukin-lβ, which are known to activate the sphingomyelin turnover leading to ceramide generation, also induced apoptosis mimicking the effects of ceramide. These findings propose ceramide as an activator of the suicidal program in Y79 cells. [ABSTRACT FROM AUTHOR]

In this study, we have demonstrated that human retinoblastoma Y79 cells produce insulin-like growth factors (IGF's) type I and type II and release them into the medium. We have also ascertained, by means of competitive studies and cross-linking procedure, that Y79 cells contain the type-I IGF receptor (IGF-IR). Furthermore, surface-bound IGF-l is internalised by the receptor, then degraded to amino acids. Insulin, IGF-I and IGF-II caused down-regulation of IGF-IR; the effect is concentration and time dependant. Scatchard analysis demonstrated that incubation with insulin markedly decreased the binding capacity measured for IGF-l while the apparent Kd value calculated for IGF-I binding was not significantly modified. IGF-I, IGF-Il and insulin induced tyrosine phosphorylation of IGF-IR. Tyrosine phosphorylation of this receptor with, however, a less strong signal, was detectable even in cells cultured in serum-free medium without the addition of any exogenous growth factor. Similar results have been found concerning the tyrosine phosphorylation of insulin receptor substrate-I (IRS-I). Tyrosine phosphorylation of both IGF-IR and IRS-I, either under basal conditions or after stimulation with growth factors, was strongly inhibited when α-IR3, a monoclonal antibody to IGF-IR, was added to the culture. IGF-I was capable of inducing Y79 cell proliferation and its effect was entirely inhibited by the addition of α-lR3. This antibody also markedly reduced the proliferation of Y79 cells cultured in serum-free medium not supplemented with stimulatory factors. Our results indicate that IGF-I and IGF-IR mediate an autocrine growth mechanism in Y79 cells. [ABSTRACT FROM AUTHOR]

This paper deals with the apoptotic effect exerted in human retinoblastoma Y79 cells by a number of compounds. A remarkable effect was observed after treatment with DNA-damaging agents, such as camptothecin, etoposide, cisplatin and carboplatin; camptothecin was found to be the most efficacious. Treatment with these compounds induced the appearance of morphological features of apoptosis in the cells together with the distinct fragmentation of DNA, as shown by agarose gel electrophoresis. These effects were also accompanied by a remarkable increase in the level of p53. Many other compounds, which are not DNA-damaging agents, induced the morphological features of apoptosis but none of them were capable of increasing the level of p53. Among these compounds, Taxol, suramin and sodium butyrate also stimulated the oligonucleosomal fragmentation of DNA, while C2-ceramide, a cell-permeable analogue of ceramide, and vitamin D3 were not effective in the induction of DNA laddering in Y79 cells. Apoptosis was dependent on macromolecular synthesis with all the compounds tested. [ABSTRACT FROM AUTHOR]

In chick embryo retinas, cultured in serum-free medium lacking L-glutamine, IGF-I, IGF-II and insulin induced apoptotic DNA fragmentation and cell death, IGF-I being the most efficacious compound. The apoptotic effect, which was particularly evident in retinas removed from 7-day-old chick embryos, declined with the age of the embryos and disappeared after day 11. Apoptosis appeared after a time lag of 8h and then increased with time up to 16 h. Cycloheximide, an inhibitor of protein synthesis, was capable of entirely abolishing apoptotic cell death. The effect induced by IGFs or insulin was suppressed by the addition of glutamine. Cytokine-mediated apoptosis was also observed after withdrawal of phosphate. We suggest that IGFs or insulin may produce, in retinas cultured in medium lacking L-glutamine or phosphate, a conflict of signals that could be lethal for retinal cells. [ABSTRACT FROM AUTHOR]