Introduction to the Toxins special issue on dietary and non-dietary phytochemicals and cancer

The role of many phytochemicals in the modulation of the carcinogenesis process has been well documented by combining in vitro and animal studies, as well as epidemiological evidence. When acting in synergy, phytochemicals exert potential anti-cancer properties, and much progress has been made in defining their many biological activities at the molecular level. However, an interesting feature in the field of phytochemicals and cancer is the role of some phytochemicals in promoting cancer development. This Special Issue of Toxins aims to provide a comprehensive look at the contribution of dietary and non-dietary phytochemicals to cancer development and at the molecular mechanisms by which phytochemicals inhibit or promote cancer.[...]

Overview of the Anticancer Potential of the "King of Spices" Piper nigrum and Its Main Constituent Piperine

The main limits of current anticancer therapy are relapses, chemoresistance, and toxic effects resulting from its poor selectivity towards cancer cells that severely impair a patient's quality of life. Therefore, the discovery of new anticancer drugs remains an urgent challenge. Natural products represent an excellent opportunity due to their ability to target heterogenous populations of cancer cells and regulate several key pathways involved in cancer development, and their favorable toxicological profile. Piper nigrum is one of the most popular spices in the world, with growing fame as a source of bioactive molecules with pharmacological properties. The present review aims to provide a comprehensive overview of the anticancer potential of Piper nigrum and its major active constituents-not limited to the well-known piperine-whose undeniable anticancer properties have been reported for different cancer cell lines and animal models. Moreover, the chemosensitizing effects of Piper nigrum in association with traditional anticancer drugs are depicted and its toxicological profile is outlined. Despite the promising results, human studies are missing, which are crucial for supporting the efficacy and safety of Piper nigrum and its single components in cancer patients

The Alcoholic Bark Extract of Terminalia Arjuna Exhibits Cytotoxic and Cytostatic Activity on Jurkat Leukemia Cells

Abstract: Background: Natural products are characterized by complex chemical composition and are capable of concurrently modulate several signalling pathways. Considering the biological com- plexity of carcinogenesis, natural products represent key components of the therapeutic armamen- tarium for oncological diseases. The bark of Terminalia arjuna is used in traditional Ayurvedic medicine for its astringent, expectorant, cardiotonic, styptic, and antidysenteric properties. Along- side its traditional uses, Terminalia arjuna exhibits different biological activities including an- timutagenic and anticarcinogenic. Objective: This study was designed to evaluate the toxic effects of an alcoholic extract obtained from the bark of T. arjuna on a human T-lymphoblastic cell line (Jurkat). We explored the phyto- chemical composition and investigated the cytotoxic, cytostatic, genotoxic, and anti-genotoxic effects. Methods: The phytochemical composition was analyzed using spectrophotometric methods; all the biological endpoints were assessed through flow cytometry. Results: The phytochemical screening showed that polyphenols represent about 64% of the extract. Moreover, the extract was cytotoxic on Jurkat cells by inducing both apoptosis and necrosis and blocked the cell cycle in the G2/M phase. Additionally, it was found that the extract lacks any geno- toxic effect, but was not effective in protecting Jurkat cells from the DNA damage induced by H2O2 and etoposide. Conclusion: The results of our study show the toxic effects of Terminalia arjuna on Jurkat cells and confirm the pivotal role played by natural compounds in the oncological field. Further studies should be performed to better understand its clinical potential and deepen its toxicological profile

Janus Kinase Inhibitors and Coronavirus Disease (COVID)-19: Rationale, Clinical Evidence and Safety Issues

: We are witnessing a paradigm shift in drug development and clinical practice to fight the novel coronavirus disease (COVID-19), and a number of clinical trials have been or are being testing various pharmacological approaches to counteract viral load and its complications such as cytokine storm. However, data on the effectiveness of antiviral and immune therapies are still inconclusive and inconsistent. As compared to other candidate drugs to treat COVID-19, Janus Kinase (JAK) inhibitors, including baricitinib and ruxolitinib, possess key pharmacological features for a potentially successful repurposing: convenient oral administration, favorable pharmacokinetic profile, multifunctional pharmacodynamics by exerting dual anti-inflammatory and anti-viral effects. Baricitinib, originally approved for rheumatoid arthritis, received Emergency Use Authorization in November 2020 by the Food and Drug Administration in combination with remdesivir for the treatment of COVID-19 in hospitalized patients ≥ 2 years old who require supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation. By July 2021, the European Medicines Agency is also expected to issue the opinion on whether or not to extend its use in hospitalised patients from 10 years of age who require supplemental oxygen. Ruxolitinib, approved for myelofibrosis, was prescribed in patients with COVID-19 within an open-label Emergency Expanded Access Plan. This review will address key milestones in the discovery and use of JAK inhibitors in COVID-19, from artificial intelligence to current clinical evidence, including real world experience, and critically appraise emerging safety issues, namely infections, thrombosis, and liver injury. An outlook to ongoing studies (clinicaltrials.gov) and unpublished pharmacovigilance data is also offered

Exercise and Oxidative Stress Biomarkers among Adult with Cancer: A Systematic Review

Evidence shows that exercise can have a favourable effect in cancer patients. The exercise's clinical benefits are likely to concern multiple interrelated biological pathways, among which oxidative stress plays a key role. Regular training can induce an adaptive response that strengthens the antioxidative status of the body. To formulate public health recommendations regarding the optimal exercise prescription for cancer patients, a detailed understanding is needed regarding the effect of exercise on variables linked to oxidative stress and antioxidant status of patients. The goal of this systematic review, based on PRISMA, was to explore and critically analyse the evidence regarding the efficacy of exercise on oxidative stress biomarkers among people with cancer. Study search was conducted in the following databases: PubMed, Cochrane, CINAHL, Embase, PEDro, and SPORTDiscus. The studies' quality was assessed with the Cochrane risk-of-bias tool and STROBE scale. After identification and screening steps, 10 articles were included. The findings provide an encouraging picture of exercise, including resistance training and aerobic activities, in people with cancer. The exercise improved the indicators of the total antioxidant capacity, increased the antioxidant enzymes' activity, or reduced the biomarkers of oxidative damage in various forms of cancer such as breast, lung, head, and neck Regarding oxidative DNA damage, the role of exercise intervention has been difficult to assess. The heterogeneity of study design and the plethora of biomarkers measured hampered the comparison of the articles. This limited the possibility of establishing a comprehensive conclusion on the sensitivity of biomarkers to estimate the exercise's benefits. Further high-quality studies are required to provide data regarding oxidative stress biomarkers responding to exercise. This information will be useful to assess the efficacy of exercise in people with cancer and support the appropriate prescription of exercise in anticancer strategy

Discovery of Sulforaphane as an Inducer of Ferroptosis in U-937 Leukemia Cells: Expanding Its Anticancer Potential

In recent years, natural compounds have emerged as inducers of non-canonical cell death. The isothiocyanate sulforaphane (SFN) is a well-known natural anticancer compound with remarkable pro-apoptotic activity. Its ability to promote non-apoptotic cell-death mechanisms remains poorly investigated. This work aimed to explore the capacity of SFN to induce non-apoptotic cell death modalities. SFN was tested on different acute myeloid leukemia cell lines. The mechanism of cell death was investigated using a multi-parametric approach including fluorescence microscopy, western blotting, and flow cytometry. SFN triggered different cell-death modalities in a dose-dependent manner. At 25 μM, SFN induced caspase-dependent apoptosis and at 50 μM ferroptosis was induced through depletion of glutathione (GSH), decreased GSH peroxidase 4 protein expression, and lipid peroxidation. In contrast, necroptosis was not involved in SFN-induced cell death, as demonstrated by the non-significant increase in phosphorylation of receptor-interacting protein kinase 3 and phosphorylation of the necroptotic effector mixed lineage kinase domain-like pseudokinase. Taken together, our results suggest that the antileukemic activity of SFN can be mediated via both ferroptotic and apoptotic cell death modalities

O CUIDADO EM SAÚDE E AS IMPLICAÇÕES PARA OS CUIDADORES DOMICILIARES

RESUMO: O artigo trata da temática do cuidado domiciliar em saúde, modalidade de atendimento que tem crescido em vários países, impulsionada pelas transições demográficas e epidemiológicas dos últimos anos. Com foco em duas experiências, o trabalho apresenta os resultados de uma pesquisa com o objetivo de analisar o perfil dos cuidadores de dois programas de atenção em saúde domiciliar sendo, um público e outro privado desenvolvido em cidades localizadas na Região da Grande Florianópolis. Trata-se de uma pesquisa qualitativa com aplicação de entrevistas com cuidadores de pessoas em internação domiciliar. Como principais resultados aponta-se que a família tem sido cada vez mais responsabilizada pelo cuidado em saúde, principalmente as mulheres alterando a dinâmica familiar que implica nas condições objetivas de vida

Curcumin-1,2,3-Triazole Conjugation for Targeting the Cancer Apoptosis Machinery

The burden of neoplastic diseases is widely recognized as a severe cause of mortality. The clinical inadequacy of most anticancer therapeutics urgently prompted intense drug discovery efforts toward the identification of new chemical entities endowed with a potent and safe antitumor profile. In this scenario, targeting cancer cells apoptosis machinery has emerged as a relevant strategy, useful for tackling the emergence of drug resistance. On this basis, a small library of naturally inspired hybrid molecules was obtained by combining, through a click chemistry approach, "privileged" synthons such as curcumin scaffold and 1,2,3-triazole building block. Compound1, bearing apara-fluoro phenyl moiety, showed low-micromolar potency against T acute lymphoblastic leukemia cell growth. More in-depth biologic studies demonstrated, for this analog, cell death-inducing properties associated with its capability to simultaneously activate both the receptor and the mitochondrial apoptosis cascades. This peculiar behavior offers promises for achieving an expanded anticancer effect, namely intense cytotoxic response coupled with reduced predisposition of chemoresistance insurgence. Altogether, this study allowed the identification of compound1as a lead compound worth to be progressed as an anticancer drug candidate

Vaccination with early ferroptotic cancer cells induces efficient antitumor immunity

Background: Immunotherapy represents the future of clinical cancer treatment. The type of cancer cell death determines the antitumor immune response and thereby contributes to the efficacy of anticancer therapy and long-term survival of patients. Induction of immunogenic apoptosis or necroptosis in cancer cells does activate antitumor immunity, but resistance to these cell death modalities is common. Therefore, it is of great importance to find other ways to kill tumor cells. Recently, ferroptosis has been identified as a novel, iron-dependent form of regulated cell death but whether ferroptotic cancer cells are immunogenic is unknown. Methods: Ferroptotic cell death in murine fibrosarcoma MCA205 or glioma GL261 cells was induced by RAS-selective lethal 3 and ferroptosis was analyzed by flow cytometry, atomic force and confocal microscopy. ATP and high-mobility group box 1 (HMGB1) release were detected by luminescence and ELISA assays, respectively. Immunogenicity in vitro was analyzed by coculturing of ferroptotic cancer cells with bone-marrow derived dendritic cells (BMDCs) and rate of phagocytosis and activation/maturation of BMDCs (CD11c(+)CD86(+), CD11c(+)CD40(+), CD11c(+)MHCII(+), IL-6, RNAseq analysis). The tumor prophylactic vaccination model in immune-competent and immune compromised (Rag-2(-/-)) mice was used to analyze ferroptosis immunogenicity. Results: Ferroptosis can be induced in cancer cells by inhibition of glutathione peroxidase 4, as evidenced by confocal and atomic force microscopy and inhibitors' analysis. We demonstrate for the first time that ferroptosis is immunogenic in vitro and in vivo. Early, but not late, ferroptotic cells promote the phenotypic maturation of BMDCs and elicit a vaccination-like effect in immune-competent mice but not in Rag-2(-/-) mice, suggesting that the mechanism of immunogenicity is very tightly regulated by the adaptive immune system and is time dependent. Also, ATP and HMGB1, the best-characterized damage-associated molecular patterns involved in immunogenic cell death, have proven to be passively released along the timeline of ferroptosis and act as immunogenic signal associated with the immunogenicity of early ferroptotic cancer cells. Conclusions: These results pave the way for the development of new therapeutic strategies for cancers based on induction of ferroptosis, and thus broadens the current concept of immunogenic cell death and opens the door for the development of new strategies in cancer immunotherapy

Effects of a commercially available branched-chain amino acid-alanine-carbohydrate-based sports supplement on perceived exertion and performance in high intensity endurance cycling tests

Background:Sports nutritional supplements containing branched-chain amino acids (BCAA) have been widelyreported to improve psychological and biological aspects connected to central fatigue and performance inendurance exercise, although the topic is still open to debate. The aim of the present study was to determinewhether the intake of a commercially available BCAA-based supplement, taken according to the manufacturer’srecommendations, could affect the rating of perceived exertion (RPE) and performance indexes at the beginning(1d) and end of a 9-week (9w) scheduled high intensity interval training program, with an experimental approachintegrating the determination of psychometric, performance, metabolic and blood biochemical parameters.Methods:This was a randomized double-blind placebo-controlled study. Thirty-two untrained, healthy young adults(20 males and 12 female) were enrolled. A high-intensity endurance cycling (HIEC) test was used to induce fatigue inthe participants: HIEC consisted in ten 90 s sprints interspersed by ten 3 min recovery phases and followed by a finalstep time to exhaustion was used. In parallel with RPE, haematological values (creatine kinase, alanine, BCAA,tryptophan, ammonia and glucose levels), and performance indexes (maximal oxygen consumption - VO2max,powerassociated with lactate thresholds - WLT1,WLT2and time to exhaustion - TTE) were assessed. All subject took thesupplement (13.2 g of carbohydrates; 3.2 g of BCAA and 1.6 g of L-alanine per dose) or placebo before each test andtraining session. Dietary habits and training load were monitored during the entire training period.Results:The administration of the supplement (SU) at 1d reduced RPE by 9% during the recovery phase, as comparedto the placebo (PL); at 9w the RPE scores were reduced by 13 and 21% during the sprint and recovery phase,respectively; at 9w, prolonged supplement intake also improved TTE and TRIMP. SU intake invariably promoted a rapidincrease (within 1 h) of BCAA serum blood levels and prevented the post-HIEC tryptophan: BCAA ratio increase foundin the PL group, at both 1d and 9w. There was no difference in dietary habits between groups and those habits didnot change over time; no difference in glycemia was found between SU and PL. VO2max,WLT1and WLT2valuesimproved over time, but were unaffected by supplement intake. Conclusions:On the whole, these results suggest that i) the intake of the BCAA-based commercially availablesupplement used in this study reduces RPE as a likely consequence of an improvement in the serum tryptophan: BCAAratio; ii) over time, reduced RPE allows subjects to sustain higher workloads, leading to increased TRIMP and TTE