Molecular engineering of a spheroid-penetrating phage nanovector for photodynamic treatment of colon cancer cells.

Photodynamic therapy (PDT) represents an emerging strategy to treat various malignancies, including colorectal cancer (CC), the third most common cancer type. This work presents an engineered M13 phage retargeted towards CC cells through pentavalent display of a disulfide-constrained peptide nonamer. The M13CC nanovector was conjugated with the photosensitizer Rose Bengal (RB), and the photodynamic anticancer effects of the resulting M13CC-RB bioconjugate were investigated on CC cells. We show that upon irradiation M13CC-RB is able to impair CC cell viability, and that this effect depends on i) photosensitizer concentration and ii) targeting efficiency towards CC cell lines, proving the specificity of the vector compared to unmodified M13 phage. We also demonstrate that M13CC-RB enhances generation and intracellular accumulation of reactive oxygen species (ROS) triggering CC cell death. To further investigate the anticancer potential of M13CC-RB, we performed PDT experiments on 3D CC spheroids, proving, for the first time, the ability of engineered M13 phage conjugates to deeply penetrate multicellular spheroids. Moreover, significant photodynamic effects, including spheroid disruption and cytotoxicity, were readily triggered at picomolar concentrations of the phage vector. Taken together, our results promote engineered M13 phages as promising nanovector platform for targeted photosensitization, paving the way to novel adjuvant approaches to fight CC malignancies.

Peanut (Arachis hypogaea L.) seeds and by-products in metabolic syndrome and cardiovascular disorders: A systematic review of clinical studies.

BACKGROUND: Cardiovascular disease (CVDs) is the leading cause of death worldwide. The main risk factors are hypertension, diabetes, obesity, and increased serum lipids. The peanut (Arachis hypogaea L.), also known as the groundnut, goober, pindar, or monkey nut, belongs to the Fabaceae family and is the fourth most cultivated oilseed in the world. The seeds and skin of peanuts possess a rich phytochemical profile composed of antioxidants, such as phenolic acids, stilbenes, flavonoids, and phytosterols. Peanut consumption can provide numerous health benefits, such as anti-obesity, antidiabetic, antihypertensive, and hypolipidemic effects. Accordingly, peanuts have the potential to treat CVD and counteract its risk factors. PURPOSE: This study aims to critically evaluate the effects of peanuts on metabolic syndrome (MetS) and CVD risk factors based on clinical studies. METHOD: This review includes studies indexed in MEDLINE-PubMed, COCHRANE, and EMBASE, and the Preferred Reporting Items for a Systematic Review and Meta-Analysis guidelines were adhered to. RESULTS: Nineteen studies were included and indicated that the consumption of raw peanuts or differing forms of processed foods containing peanut products and phytochemicals could improve metabolic parameters, such as glycemia, insulinemia, glycated hemoglobin, lipids, body mass index, waist circumference, atherogenic indices, and endothelial function. CONCLUSION: We propose that this legume and its products be used as a sustainable and low-cost alternative for the prevention and treatment of MetS and CVD. However, further research with larger sample sizes, longer intervention durations, and more diverse populations is needed to understand the full benefit of peanut consumption in MetS and CVD.

Antimutagenicity and Antioxidant Activity of Castanea sativa Mill. Bark Extract.

Castanea sativa Mill. (Cs), a plant traditionally employed in nutrition and to treat various respiratory and gastrointestinal infections, possesses cancer chemopreventive characteristics. In particular, Cs bark extract previously demonstrated antiproliferative and pro-apoptotic activities against a leukemic lymphoblastic cell line. Starting from this evidence, the aim of this paper was to investigate the possibility to affect also the earlier phases of the carcinogenic process by evaluating Cs bark extract's antimutagenic properties, in particular using the "In Vitro Mammalian Cell Micronucleus Test" on TK6 cells performed by flow cytometry. For this purpose, since an ideal chemopreventive agent should be virtually nontoxic, the first step was to exclude the extract's genotoxicity. Afterwards, the antimutagenic effect of the extract was evaluated against two known mutagens, the clastogen mitomycin C (MMC) and the aneugen vinblastine (VINB). Our results indicate that Cs bark extract protected cells from MMC-induced damage (micronuclei frequency fold increase reduction from 2.9 to 1.8) but not from VINB. Moreover, we demonstrated that Cs bark extract was a strong antioxidant and significantly reduced MMC-induced ROS levels by over 2 fold. Overall, our research supports the assumption that Cs bark extract can counteract MMC mutagenicity by possibly scavenging ROS production.

Ten Years of Research on Fucoidan and Cancer: Focus on Its Antiangiogenic and Antimetastatic Effects.

Angiogenesis and metastasis represent two challenging targets to combat cancer development in the later stages of its progression. Numerous studies have indicated the important role of natural products in blocking tumor angiogenesis signaling pathways in several advanced tumors. In recent years, the marine polysaccharides fucoidans emerged as promising anticancer compounds showing potent antitumor activity in both in vitro and in vivo models of different types of cancers. The objective of this review is to focus on the antiangiogenic and antimetastatic activities of fucoidans with special emphasis on preclinical studies. Independently from their source, fucoidans inhibit several angiogenic regulators, primarily vascular endothelial growth factor (VEGF). A glance towards fucoidans' ongoing clinical trials and pharmacokinetic profile is provided to present the main challenges that still need to be addressed for their bench-to-bedside translation.

Novel Insights in the Potential of Halogenated Polyketide-Peptide Molecules as Lead Compounds in Cancer Drug Discovery.

In this interdisciplinary study, we selected two compounds, namely, smenamide A, a peptide-polyketide, and smenolactone D, a polyketide, as models because they are representative of two different classes of molecules isolated from the marine sponge Smenospongia aurea. The organic extract of Smenospongia aurea was analyzed using a combination of high-resolution LC-MS/MS and molecular networking, a recently developed method for automated LC-MS data analysis. The analyses were targeted to highlight clusters made by chlorinated compounds present in the extracts. Then, the two model compounds were analyzed for their bioactivity. Data reported here show that smenamide A did not exhibit a cytotoxic effect, while smenolactone D was cytotoxic on different tumor cell lines and was able to induce different types of cell death, including ferroptosis and apoptosis.

Identification of Blood Transport Proteins to Carry Temoporfin: A Domino Approach from Virtual Screening to Synthesis and In Vitro PDT Testing.

Temoporfin (mTHPC) is one of the most promising photosensitizers used in photodynamic therapy (PDT). Despite its clinical use, the lipophilic character of mTHPC still hampers the full exploitation of its potential. Low solubility in water, high tendency to aggregate, and low biocompatibility are the main limitations because they cause poor stability in physiological environments, dark toxicity, and ultimately reduce the generation of reactive oxygen species (ROS). Applying a reverse docking approach, here, we identified a number of blood transport proteins able to bind and disperse monomolecularly mTHPC, namely apohemoglobin, apomyoglobin, hemopexin, and afamin. We validated the computational results synthesizing the mTHPC-apomyoglobin complex (mTHPC@apoMb) and demonstrated that the protein monodisperses mTHPC in a physiological environment. The mTHPC@apoMb complex preserves the imaging properties of the molecule and improves its ability to produce ROS via both type I and type II mechanisms. The effectiveness of photodynamic treatment using the mTHPC@apoMb complex was then demonstrated in vitro. Blood transport proteins can be used as molecular "Trojan horses" in cancer cells by conferring mTHPC (i) water solubility, (ii) monodispersity, and (iii) biocompatibility, ultimately bypassing the current limitations of mTHPC.

Light-Enhanced Cytotoxicity of Doxorubicin by Photoactivation.

The combination of photodynamic therapy with chemotherapy (photochemotherapy, PCT) can lead to additive or synergistic antitumor effects. Usually, two different molecules, a photosensitizer (PS) and a chemotherapeutic drug are used in PCT. Doxorubicin is one of the most successful chemotherapy drugs. Despite its high efficacy, two factors limit its clinical use: severe side effects and the development of chemoresistance. Doxorubicin is a chromophore, able to absorb light in the visible range, making it a potential PS. Here, we exploited the intrinsic photosensitizing properties of doxorubicin to enhance its anticancer activity in leukemia, breast, and epidermoid carcinoma cells, upon irradiation. Light can selectively trigger the local generation of reactive oxygen species (ROS), following photophysical pathways. Doxorubicin showed a concentration-dependent ability to generate peroxides and singlet oxygen upon irradiation. The underlying mechanisms leading to the increase in its cytotoxic activity were intracellular ROS generation and the induction of necrotic cell death. The nuclear localization of doxorubicin represents an added value for its use as a PS. The use of doxorubicin in PCT, simultaneously acting as a chemotherapeutic agent and a PS, may allow (i) an increase in the anticancer effects of the drug, and (ii) a decrease in its dose, and thus, its dose-related adverse effects.

In Vitro Investigation of the Anticancer Properties of Ammodaucus Leucotrichus Coss. & Dur.

Little is known about the pharmacological activity of Ammodaucus leucotrichus Coss. & Dur., a small annual species that grows in the Saharan and sub-Saharan countries. In the present study, we investigated whether the standardized ethanolic extract of A. leucotrichus fruits and R-perillaldehyde, a monoterpenoid isolated from A. leucotrichus fruits, are able to affect different processes involved in different phases of cancer development. In particular, we explored their genoprotective, proapoptotic, antiproliferative, and cytodifferentiating potential on different human cell models. We analyzed the genoprotective and proapoptotic activity on human lymphoblast cells (TK6) using the micronucleus test, and the cytodifferentiation effects on human promyelocytic cells (HL60) through the evaluation of different markers of differentiation forward granulocytes or monocytes. The results showed that the extract and perillaldehyde were able to induce apoptosis and protect from clastogen-induced DNA damage. To our best knowledge, this is the first report on the ability of A. leucotrichus and perillaldehyde to induce apoptosis and protect DNA from the toxicity of different compounds. Data reported in this work are the starting point for their pharmacological use. Going forward, efforts to determine their effects on other events associated with cancer development, such as angiogenesis and metastasization, will provide important information and improve our understanding of their potential in cancer therapy.

Marine-Derived Compounds Targeting Topoisomerase II in Cancer Cells: A Review.

Cancer affects more than 19 million people and is the second leading cause of death in the world. One of the principal strategies used in cancer therapy is the inhibition of topoisomerase II, involved in the survival of cells. Side effects and adverse reactions limit the use of topoisomerase II inhibitors; hence, research is focused on discovering novel compounds that can inhibit topoisomerase II and have a safer toxicological profile. Marine organisms are a source of secondary metabolites with different pharmacological properties including anticancer activity. The objective of this review is to present and discuss the pharmacological potential of marine-derived compounds whose antitumor activity is mediated by topoisomerase II inhibition. Several compounds derived from sponges, fungi, bacteria, ascidians, and other marine sources have been demonstrated to inhibit topoisomerase II. However, some studies only report docking interactions, whereas others do not fully explain the mechanisms of topoisomerase II inhibition. Further in vitro and in vivo studies are needed, as well as a careful toxicological profile evaluation with a focus on cancer cell selectivity.

Marine Compounds, Mitochondria, and Malignancy: A Therapeutic Nexus.

The marine environment is important yet generally underexplored. It contains new sources of functional constituents that can affect various pathways in food processing, storage, and fortification. Bioactive secondary metabolites produced by marine microorganisms may have significant potential applications for humans. Various components isolated from disparate marine microorganisms, including fungi, microalgae, bacteria, and myxomycetes, showed considerable biological effects, such as anticancer, antioxidant, antiviral, antibacterial, and neuroprotective activities. Growing studies are revealing that potential anticancer effects of marine agents could be achieved through the modulation of several organelles. Mitochondria are known organelles that influence growth, differentiation, and death of cells via influencing the biosynthetic, bioenergetic, and various signaling pathways related to oxidative stress and cellular metabolism. Consequently, mitochondria play an essential role in tumorigenesis and cancer treatments by adapting to alterations in environmental and cellular conditions. The growing interest in marine-derived anticancer agents, combined with the development and progression of novel technology in the extraction and cultures of marine life, led to revelations of new compounds with meaningful pharmacological applications. This is the first critical review on marine-derived anticancer agents that have the potential for targeting mitochondrial function during tumorigenesis. This study aims to provide promising strategies in cancer prevention and treatment.

On the toxicity of e-cigarettes consumption: Focus on pathological cellular mechanisms.

Tobacco smoking remains without a doubt one of the leading causes of premature death worldwide. In combination with conventional protocols for smoking cessation, e-cigarettes have been proposed as a useful tool to quit smoking. Advertised as almost free of toxic effects, e-cigarettes have rapidly increased their popularity, becoming a sought-after device, especially among young people. Recently some health concerns about e-cigarette consumption are being raised. It is well known that they can release several toxic compounds, some of which are carcinogenic to humans, and emerging results are now outlining the risks related to the onset of respiratory and cardiovascular diseases and even cancer. The present review shows the emerging evidence about the role of technical components of the devices, the e-liquid composition as well as customization by consumers. The primary topics we discuss are the main toxicological aspects associated with e-cigarette consumption, focusing on the molecular pathways involved. Here it will be shown how exposure to e-cigarette aerosol induces stress/mitochondrial toxicity, DNA breaks/fragmentation following the same pathological pathways triggered by tobacco smoke, including the deregulation of molecular signalling axis associated with cancer progression and cell migration. Risk to fertility and pregnancy, as well as cardiovascular risk associated with e-cigarette use, have also been reported.

Characterization of the Biological Activity of the Ethanolic Extract from the Roots of Cannabis sativa L. Grown in Aeroponics.

Cannabis sativa var. Kompolti, a variety routinely used for food production purposes, is characterized by a low concentration of psychoactive molecules, although containing many other biologically attractive metabolites in all parts of the plant, including the roots. In the present work, we evaluate the specific biological activities of the roots' extract from plants cultivated through aeroponics, an affordable and reliable method facilitating the isolation and processing of roots, with the advantage of being suitable for industrial scale-up. Furthermore, aeroponics results in an increased net accumulation of the most biologically attractive constituents (ß-sitosterol, friedelin and epi-friedelanol) found in the roots. The ethanolic extract of the aeroponic roots of C. sativa (APEX) and its separate components are studied to evaluate their anti-inflammatory (modulation of the expression level of specific markers upon LPS stimulation in U937 cells, such as IL-6, IL-8, TNF-α, IkB-α, iNOS, IRAK-1 and miR-146a) and antioxidant (in either acellular or cellular settings) activities. The APEX anti-inflammatory and antioxidant capacities are also functionally benchmarked using the wound-healing assay. On the whole, the data obtained show that APEX and its main components showed significant anti-inflammatory and antioxidant activities, which may render the exploitation of roots as a source of natural antioxidants and anti-inflammatory agents highly attractive, with the additional technical and economic advantages of aeroponics compared to soil cultivation.

Anticancer potential of allicin: A review.

Phytochemicals have attracted attention in the oncological field because they are biologically friendly and have relevant pharmacological activities. Thanks to the intense and unique spicy aroma, garlic is one of the most used plants for cooking. Its consumption is correlated to health beneficial effects towards several chronic diseases, such as cancer, mainly attributable to allicin, a bioactive sulfur compound stored in different plant parts in a precursor form. The objective of this review is to present and critically discuss the chemistry and biosynthesis of allicin, its pharmacokinetic profile, its anticancer mechanisms and molecular targets, and its selectivity towards tumor cells. The research carried out so far revealed that allicin suppresses the growth of different types of tumors. In particular, it targets many signaling pathways associated with cancer development. Future research directions are also outlined to further characterize this promising natural product.

Synthesis, in vitro cytotoxicity, molecular docking and ADME study of some indolin-2-one linked 1,2,3-triazole derivatives.

In pursuit of an anticancer lead, a library of 1,2,3-triazole derivatives (7a-x) was prepared, characterized and screened for in vitro cytotoxicity in different cell lines. Most of the compounds proved to be cytotoxic with IC50 values in the low micromolar range. Further studies showed that the most active compound 7c induces caspase-dependent apoptosis in Jurkat cells by activating both the intrinsic and the extrinsic apoptotic pathways and perturbs cell-cycle progression. Moreover, 7c did not show any genotoxic activity. Molecular docking simulations were performed against epidermal growth factor receptor (EGFR). Docking experiments showed that, compounds 7c, 7o and 7 v bind within active sites of epidermal growth factor receptor EGFR (Pdb ID: 6P8Q) by strong hydrogen bonds with residue MET793, Pi-Sulfur with residue MET790 and Pi-Alkyl type interactions with residues LEU788, ALA743. The SwissADME webserver investigation suggested that most of the synthesized compounds follow the rules of drug-likeness.

The Evaluation of Physical Activity Habits in North Italian People before and during COVID-19 Quarantine: A Pilot Study.

COVID-19 caused a global pandemic state. Many governments enforced quarantines which had several negative effects on peoples' health. The present study aimed to investigate the social restriction effects on the physical activity (PA) habits of north Italian people and understand whether PA was a healthy support during lockdown. Moreover, it analysed some possible strategies which could promote an active lifestyle when the pandemic ends. A new questionnaire was proposed (Cronbach's alpha = 0.816), and 309 surveys were collected in people from two Italian regions (53.72% from Emilia-Romagna and 46.28% from Veneto; 62.46% were female and 37.54% were male; and the age range was 46.67 ± 15.45 years). The number of younger people (≤25 years) who practiced PA increased during lockdown (p < 0.01); in addition, they were more active than people who were 26-35 years old (p < 0.001). The training frequency before COVID-19 was higher in females than males (p = 0.01), and the frequency of weekly PA increased during lockdown in groups aged 26-35 years (p < 0.001). Despite the fact that PA was a psychological support during lockdown (p < 0.001), performing forced home-based PA demotivated people (p < 0.001). Finally, people thought to practice outdoor PA (OPA) at the end of lockdown because they wanted to retain contact with nature, which can improve psychological well-being. Future strategies to promote OPA may increase participation in PA, especially in older people.

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.

The Anti- and Pro-Tumorigenic Role of Microbiota and Its Role in Anticancer Therapeutic Strategies.

Human gut microbiota physiologically and actively participates as a symbiont to a wide number of fundamental biological processes, such as absorption and metabolism of nutrients, regulation of immune response and inflammation; gut microbiota plays also an antitumor role. However, dysbiosis, resulting from a number of different situations-dysmicrobism, infections, drug intake, age, diet-as well as from their multiple combinations, may lead to tumorigenesis and is associated with approximately 20% of all cancers. In a diagnostic, prognostic, therapeutic, and epidemiological perspective, it is clear that the bifaceted role of microbiota needs to be thoroughly studied and better understood. Here, we discuss the anti- and pro-tumorigenic potential of gut and other microbiota districts along with the causes that may change commensal bacteria from friend to foes.

Perillaldehyde is a new ferroptosis inducer with a relevant clinical potential for acute myeloid leukemia therapy.

Ferroptosis induction is an emerging strategy to treat cancer and contrast the tricky issue of chemoresistance, which can arise towards apoptosis. This work elucidates the anticancer mechanisms evoked by perillaldehyde, a monoterpenoid isolated from Ammodaucus leucotrichus Coss. & Dur. We investigated and characterized its antileukemic potential in vitro, disclosing its ability to trigger ferroptosis. Specifically, perillaldehyde induced lipid peroxidation, decreased glutathione peroxidase 4 protein expression, and depleted intracellular glutathione on HL-60 promyelocytic leukemia cells. Besides, it stimulated the active secretion of ATP, one of the most crucial events in the induction of efficient anticancer response, prompting further studies to disclose its possible nature as an immunogenic cell death inducer. To preliminarily assess the clinical relevance of perillaldehyde, we tested its ability to induce cell death on patient-derived acute myeloid leukemia biopsies, recording a similar mechanism of action and potency compared to HL-60 cells. To round the study off, we tested its selectivity towards tumor cells and disclosed lower toxicity on normal cells compared to both HL-60 and acute myeloid leukemia biopsies. Altogether, these data depict a favorable risk-benefit profile for perillaldehyde and reveal its peculiar antileukemic potential, which qualifies this natural product to proceed further through the drug development pipeline.

Effect of the Marine Polyketide Plocabulin on Tumor Progression.

Marine sponges represent one of the richest sources of natural marine compounds with anticancer potential. Plocabulin (PM060184), a polyketide originally isolated from the sponge Lithoplocamia lithistoides, elicits its main anticancer properties binding tubulin, which still represents one of the most important targets for anticancer drugs. Plocabulin showed potent antitumor activity, in both in vitro and in vivo models of different types of cancers, mediated not only by its antitubulin activity, but also by its ability to block endothelial cell migration and invasion. The objective of this review is to offer a description of plocabulin's mechanisms of action, with special emphasis on the antiangiogenic signals and the latest progress on its development as an anticancer agent.

Carrying Temoporfin with Human Serum Albumin: A New Perspective for Photodynamic Application in Head and Neck Cancer.

Temoporfin (mTHPC) is approved in Europe for the photodynamic treatment of head and neck squamous cell carcinoma (HNSCC). Although it has a promising profile, its lipophilic character hampers the full exploitation of its potential due to high tendency of aggregation and a reduced ROS generation that compromise photodynamic therapy (PDT) efficacy. Moreover, for its clinical administration, mTHPC requires the presence of ethanol and propylene glycol as solvents, often causing adverse effects in the site of injection. In this paper we explored the efficiency of a new mTHPC formulation that uses human serum albumin (HSA) to disperse the photosensitizer in solution (mTHPC@HSA), investigating its anticancer potential in two HNSCC cell lines. Through a comprehensive characterization, we demonstrated that mTHPC@HSA is stable in physiological environment, does not aggregate, and is extremely efficient in PDT performance, due to its high singlet oxygen generation and the high dispersion as monomolecular form in HSA. This is supported by the computational identification of the specific binding pocket of mTHPC in HSA. Moreover, mTHPC@HSA-PDT induces cytotoxicity in both HNSCC cell lines, increasing intracellular ROS generation and the number of γ-H2AX foci, a cellular event involved in the global response to cellular stress. Taken together these results highlight the promising phototoxic profile of the complex, prompting further studies to assess its clinical potential.