A Comprehensive Review on the State of the Art of Breast Cancers in Italy.

Breast cancer (BC) currently represents one of the most prevalent cancers among women worldwide and the leading cause of cancer death among women, also negatively affecting the quality of life (QoL) in patients. Over the past two decades, BC research has led to extraordinary advances in our understanding of the disease, resulting in more effective treatments. However, its occurrence is still increasing. Several new treatments are now under development worldwide, but they are not devoid of well-- known side effects, and a great number of patients develop endocrine resistance. Nevertheless, the design and synthesis of more suitable strategies and new drugs to treat breast cancers, overcome resistance and side effects, and obtain better therapeutic outcomes are needed. In this review, we summarize the therapies and the clinical studies currently ongoing in Italy for the treatment of BCs, mainly HER2+ MBC, HER2-low MBC, and TNBC, focusing on the most recent ones, also in consideration of diverse facets, including some aspects related to QoL. Finally, some studies related to the usefulness of physical activity in BC will be cited.

An Update on Recent Studies Focusing on the Antioxidant Properties of Salvia Species.

Nutrition has crucial effects and a significant role in disease prevention. Recently, nutraceuticals have attracted much attention in scientific research due to their pleiotropic effects and relatively non-toxic behavior. Among the biological effects displayed by plants belonging to the Lamiaceae family, such as antibacterial, anticancer, anti-inflammatory, and anticholinesterase, sage is well known for its antioxidant properties and is a rich source of numerous compounds that are biologically active, amongst them polyphenols, with more than 160 types identified. In this review we summarized some of the significant studies published in the last decade reporting the most employed extraction methods and the different assays that are useful for establishing the antioxidant properties of some sage species. Even though the scientific literature contains plenty of data regarding the antioxidant properties of many sage species, further studies are needed in order to gain a deeper understanding of the mechanism of action and the compounds responsible for their antioxidant activity. Finally, it should be taken into account that the data on the antioxidant properties of sage extracts are often difficult to compare with each other, since a series of variables in the extraction procedures, the type of assay used, and standardization may affect the final result.

Complexes of Ruthenium(II) as Promising Dual-Active Agents against Cancer and Viral Infections.

Poor responses to medical care and the failure of pharmacological treatment for many high-frequency diseases, such as cancer and viral infections, have been widely documented. In this context, numerous metal-based substances, including cisplatin, auranofin, various gold metallodrugs, and ruthenium complexes, are under study as possible anticancer and antiviral agents. The two Ru(III) and Ru(II) complexes, namely, BOLD-100 and RAPTA-C, are presently being studied in a clinical trial and preclinical studies evaluation, respectively, as anticancer agents. Interestingly, BOLD-100 has also recently demonstrated antiviral activity against SARS-CoV-2, which is the virus responsible for the COVID-19 pandemic. Over the last years, much effort has been dedicated to discovering new dual anticancer-antiviral agents. Ru-based complexes could be very suitable in this respect. Thus, this review focuses on the most recent studies regarding newly synthesized Ru(II) complexes for use as anticancer and/or antiviral agents.

NHC-Ag(I) and NHC-Au(I) Complexes with N-Boc-Protected α-Amino Acidate Counterions Powerfully Affect the Growth of MDA-MB-231 Cells.

N-Heterocyclic carbene (NHC) metal complexes are attracting scientists' interest as an alluring class of metallodrugs. Indeed, the versatile functionalization of NHC ligands makes them optimal scaffolds to be developed in medicinal chemistry. Besides, amino acids are great biological ligands for metals, such as silver and gold, even though their use is still under-investigated. Aiming to shed light on the anticancer properties of this kind of complex, we investigated a series of silver and gold complexes, stabilized by NHC ligands and bearing carboxylate salts of tert-butyloxycarbonyl (Boc)-N-protected glycine and l-phenylalanine as anionic ligands. The most active complexes, AuM1Gly and AuM1Phe, powerfully affect the growth of MDA-MB-231 breast cancer cells, with IC50 values in the low nanomolar range. Further studies demonstrated the blockade of the human topoisomerase I activity and actin polymerization reaction at 0.001 µM. These unique features make these complexes very interesting and worthy to be used for future in vivo studies.

Prevalence of Cobalt in the Environment and Its Role in Biological Processes.

Cobalt (Co) is an essential trace element for humans and other animals, but high doses can be harmful to human health. It is present in some foods such as green vegetables, various spices, meat, milk products, seafood, and eggs, and in drinking water. Co is necessary for the metabolism of human beings and animals due to its key role in the formation of vitamin B12, also known as cobalamin, the biological reservoir of Co. In high concentrations, Co may cause some health issues such as vomiting, nausea, diarrhea, bleeding, low blood pressure, heart diseases, thyroid damage, hair loss, bone defects, and the inhibition of some enzyme activities. Conversely, Co deficiency can lead to anorexia, chronic swelling, and detrimental anemia. Co nanoparticles have different and various biomedical applications thanks to their antioxidant, antimicrobial, anticancer, and antidiabetic properties. In addition, Co and cobalt oxide nanoparticles can be used in lithium-ion batteries, as a catalyst, a carrier for targeted drug delivery, a gas sensor, an electronic thin film, and in energy storage. Accumulation of Co in agriculture and humans, due to natural and anthropogenic factors, represents a global problem affecting water quality and human and animal health. Besides the common chelating agents used for Co intoxication, phytoremediation is an interesting environmental technology for cleaning up soil contaminated with Co. The occurrence of Co in the environment is discussed and its involvement in biological processes is underlined. Toxicological aspects related to Co are also examined in this review.

Natural Products for the Prevention, Treatment and Progression of Breast Cancer.

In this review, we summarize the most used natural products as useful adjuvants in BC by clarifying how these products may play a critical role in the prevention, treatment and progression of this disease. BC is the leading cancer, in terms of incidence, that affects women. The epidemiology and pathophysiology of BC were widely reported. Inflammation and cancer are known to influence each other in several tumors. In the case of BC, the inflammatory component precedes the development of the neoplasm through a slowly increasing and prolonged inflammation that also favors its growth. BC therapy involves a multidisciplinary approach comprising surgery, radiotherapy and chemotherapy. There are numerous observations that showed that the effects of some natural substances, which, in integration with the classic protocols, can be used not only for prevention or integration in order to prevent recurrences and induce a state of chemoquiescence but also as chemo- and radiosensitizers during classic therapy.

Synthesis of Novel N-Heterocyclic Carbene-Ruthenium (II) Complexes, "Precious" Tools with Antibacterial, Anticancer and Antioxidant Properties.

Ruthenium N-heterocyclic carbene (Ru-NHC) complexes show interesting physico-chemical properties as catalysts and potential in medicinal chemistry, exhibiting multiple biological activities, among them anticancer, antimicrobial, antioxidant, and anti-inflammatory. Herein, we designed and synthesized a new series of Ru-NHC complexes and evaluated their biological activities as anticancer, antibacterial, and antioxidant agents. Among the newly synthesized complexes, RANHC-V and RANHC-VI are the most active against triple-negative human breast cancer cell lines MDA-MB-231. These compounds were selective in vitro inhibitors of the human topoisomerase I activity and triggered cell death by apoptosis. Furthermore, the Ru-NHC complexes' antimicrobial activity was studied against Gram-positive and -negative bacteria, revealing that all the complexes possessed the best antibacterial activity against the Gram-positive Staphylococcus aureus, at a concentration of 25 µg/mL. Finally, the antioxidant effect was assessed by DPPH and ABTS radicals scavenging assays, resulting in a higher ability for inhibiting the ABTS•+, with respect to the well-known antioxidant Trolox. Thus, this work provides encouraging insights for further development of novel Ru-NHC complexes as potent chemotherapeutic agents endowed with multiple biological properties.

5,8-Dimethyl-9H-carbazole Derivatives Blocking hTopo I Activity and Actin Dynamics.

Over the years, carbazoles have been largely studied for their numerous biological properties, including antibacterial, antimalarial, antioxidant, antidiabetic, neuroprotective, anticancer, and many more. Some of them have gained great interest for their anticancer activity in breast cancer due to their capability in inhibiting essential DNA-dependent enzymes, namely topoisomerases I and II. With this in mind, we studied the anticancer activity of a series of carbazole derivatives against two breast cancer cell lines, namely the triple negative MDA-MB-231 and MCF-7 cells. Compounds 3 and 4 were found to be the most active towards the MDA-MB-231 cell line without interfering with the normal counterpart. Using docking simulations, we assessed the ability of these carbazole derivatives to bind human topoisomerases I and II and actin. In vitro specific assays confirmed that the lead compounds selectively inhibited the human topoisomerase I and interfered with the normal organization of the actin system, triggering apoptosis as a final effect. Thus, compounds 3 and 4 are strong candidates for further drug development in multi-targeted therapy for the treatment of triple negative breast cancer, for which safe therapeutic regimens are not yet available.

Targeting Breast Cancer: An Overlook on Current Strategies.

Breast cancer (BC) is one of the most widely diagnosed cancers and a leading cause of cancer death among women worldwide. Globally, BC is the second most frequent cancer and first most frequent gynecological one, affecting women with a relatively low case-mortality rate. Surgery, radiotherapy, and chemotherapy are the main treatments for BC, even though the latter are often not aways successful because of the common side effects and the damage caused to healthy tissues and organs. Aggressive and metastatic BCs are difficult to treat, thus new studies are needed in order to find new therapies and strategies for managing these diseases. In this review, we intend to give an overview of studies in this field, presenting the data from the literature concerning the classification of BCs and the drugs used in therapy for the treatment of BCs, along with drugs in clinical studies.

Biological Activities of Ruthenium NHC Complexes: An Update.

Ruthenium N-heterocyclic carbene (NHC) complexes have unique physico-chemical properties as catalysts and a huge potential in medicinal chemistry and pharmacology, exhibiting a variety of notable biological activities. In this review, the most recent studies on ruthenium NHC complexes are summarized, focusing specifically on antimicrobial and antiproliferative activities. Ruthenium NHC complexes are generally active against Gram-positive bacteria, such as Bacillus subtilis, Staphylococcus aureus, Micrococcus luteus, Listeria monocytogenes and are seldom active against Gram-negative bacteria, including Salmonella typhimurium, Pseudomonas aeruginosa and Escherichia coli and fungal strains of Candida albicans. The antiproliferative activity was tested against cancer cell lines of human colon, breast, cervix, epidermis, liver and rat glioblastoma cell lines. Ruthenium NHC complexes generally demonstrated cytotoxicity higher than standard anticancer drugs. Further studies are needed to explore the mechanism of action of these interesting compounds.

Antimicrobial and antioxidant properties and quantitative screening of phytochemicals of Fraxinus excelsior L. and Eschscholtzia californica Cham. mother tinctures.

The antioxidant and antimicrobial activities of Fraxinus excelsior L. and Eschscholtzia californica Cham. mother tinctures against a range of foodborne bacteria were investigated to determine the major components and to analyse the action spectrum and antimicrobial effectiveness of the extracts. Results demonstrated a significant antioxidant activity of Fraxinus excelsior L. and a lower activity of Eschscholtzia californica Cham. and a good chemical phenolic composition with the highest content of flavonoids. The Fraxinus excelsior L. and Eschscholtzia californica Cham. mother tinctures demonstrated a middle-high antimicrobial activity against, respectively, 66.67% and 43.33% of all tested bacteria. The inhibitory activity showed a moderate effect on the growth of the sensitive strains in presence of extracts minimum inhibitory concentration. The synergistic actions of bioactive compounds detected in the extracts might be on the basis of antioxidant and biological activities observed and should be used in pharmaceutical, food preservation, alternative medicine and natural therapies fields.

Ancient Wheat as Promising Nutraceuticals for the Prevention of Chronic and Degenerative Diseases.

In the context of a balanced diet, wheat, mainly used as whole grains, is a good source of nutrients, including fibers and bioactive compounds. Cereals belong to the Poaceae family and are crucial for maintaining a healthy status, granted by their nutritional and chemical properties. Recent studies have demonstrated that the intake of whole grains and grain-based products may reduce the risk of oxidative stress, thus lowering chronic and age-related disorders, such as obesity, cardiovascular diseases, type II diabetes and cancer. Indeed, several studies report that regular whole grain consumption is associated with lower levels of total and LDL-cholesterol, triglycerides, fasting glucose, blood pressure and body mass index. Moreover, ancient wheat species have become increasingly interested in human health, containing several nutraceutical compounds, such as vitamins and minerals. The numerous phytochemicals present in ancient wheat (polyphenols, carotenoids, phytosterols and phenolic compounds) provide, in fact, antioxidant properties, which are essential in the prevention of various chronic and degenerative diseases. This review aims to report information on ancient wheat species, discussing their composition and nutraceutical properties compared with modern varieties and highlighting the beneficial impact on human health.

Metal Complexes with Schiff Bases: Data Collection and Recent Studies on Biological Activities.

Metal complexes play a crucial role in pharmaceutical sciences owing to their wide and significant activities. Schiff bases (SBs) are multifaceted pharmacophores capable of forming chelating complexes with various metals in different oxidation states. Complexes with SBs are extensively studied for their numerous advantages, including low cost and simple synthetic strategies. They have been reported to possess a variety of biological activities, including antimicrobial, anticancer, antioxidant, antimalarial, analgesic, antiviral, antipyretic, and antidiabetic ones. This review summarizes the most recent studies on the antimicrobial and antiproliferative activities of SBs-metal complexes. Moreover, recent studies regarding mononuclear and binuclear complexes with SBs are described, including antioxidant, antidiabetic, antimalarial, antileishmanial, anti-Alzheimer, and catecholase activities.

Exploring the anticancer and antioxidant properties of Vicia faba L. pods extracts, a promising source of nutraceuticals.

Background: Pulse crops are considered the major sources of proteins, dietary fiber, micronutrients, and bioactive phytochemicals. Among the numerous pulse crops, broad beans (Vicia faba L.) have received particular attention due to their nutraceutical, functional and economic importance. Our attention was mainly focused on the broad bean pods (VFs), which are the primary by-product of the domestic and industrial processing of broad beans and an attractive source of valuable ingredients. Methods: In order to investigate the VFs properties, the flours from broad beans of three different harvest periods were extracted with acetone, methanol and 70% aqueous ethanol and the dried extracts were analyzed, qualitatively and quantitatively, and tested for their antioxidant through DPPH and ABTS assay and anticancer activities using the MTT assay and immunofluorescence analysis. Results: The VF extracts demonstrated a good in vitro radical scavenging activity from the first stage of collection of all the V. faba L. extracts. Additionally, the extracts were tested for their cytotoxicity against a panel of cancer and normal cells and the outcomes indicated the ethanol extract as the most active against the melanoma cell line Sk-Mel-28, without affecting the viability of the normal cells. Finally, we found out that the ethanol extract interfered with the microtubules organization, leading to the cancer cells death by apoptosis.

Opuntia ficus indica (L.) Mill. An Ancient Plant Source of Nutraceuticals.

Opuntia ficus-indica (L.) Mill. (OFI) is a plant with numerous beneficial properties known in traditional medicine. It has been a domesticated plant in Latin America, Africa, Mediterranean countries, the Middle East, India and Australia. Nowadays, the research concentrates on natural compounds to lower costs and the possible side effects of synthetic compounds. The use of nutraceuticals, bioactive compounds of vegetable origin with important nutritional values, is encouraged. OFI has shown numerous activities due to its high content of antioxidants, including flavonoids and ascorbate, pigments, carotenoids and betalains, phenolic acids and other phytochemical components, such as biopeptides and soluble fibers. The most important effects of OFI are represented by the activity against acne, arthrosis, dermatosis, diabetes, diarrhea, fever, high blood pressure, prostatitis, rheumatism, stomachache, tumor, wart, allergy, wound, colitis and some viral diseases. Moreover, a promising role has been suggested in inflammatory bowel disease, colitis and metabolic syndrome. The most recent studies addressed the role of OFI in preventing and treating COVID-19 disease. In light of the above, this review summarizes the biological activities and health benefits that this plant may exert.

N-Heterocyclic Carbene (NHC) Silver Complexes as Versatile Chemotherapeutic Agents Targeting Human Topoisomerases and Actin.

In recent years, the number of people suffering from cancer has risen rapidly and the World Health Organization and U.S. and European governments have identified this pathology as a priority issue. It is known that most bioactive anticancer molecules do not target a single protein but exert pleiotropic effects, simultaneously affecting multiple pathways. In our study, we designed and synthesized a new series of silver N-heterocyclic carbene (NHC) complexes [(NHC)2 Ag]+ [AgX2 ]- (X=iodide or acetate). The new complexes were active against two human breast cancer cell lines, MCF-7 and MDA-MB-231. These compounds showed multiple target actions as anticancer, by inhibiting in vitro the activity of the human topoisomerases I and II and interfering with the cytoskeleton dynamic, as also confirmed by in silico studies. Moreover, the antimicrobial activity of these silver complexes was studied against Gram-positive/negative bacteria. These dual properties provide a two-tiered approach, making these compounds of interest to be further deepened for the development of new chemotherapeutic agents.

Triclosan: A Small Molecule with Controversial Roles.

Triclosan (TCS), a broad-spectrum antimicrobial agent, has been widely used in personal care products, medical products, plastic cutting boards, and food storage containers. Colgate Total® toothpaste, containing 10 mM TCS, is effective in controlling biofilm formation and maintaining gingival health. Given its broad usage, TCS is present ubiquitously in the environment. Given its strong lipophilicity and accumulation ability in organisms, it is potentially harmful to biohealth. Several reports suggest the toxicity of this compound, which is inserted in the class of endocrine disrupting chemicals (EDCs). In September 2016, TCS was banned by the U.S. Food and Drug Administration (FDA) and the European Union in soap products. Despite these problems, its application in personal care products within certain limits is still allowed. Today, it is still unclear whether TCS is truly toxic to mammals and the adverse effects of continuous, long-term, and low concentration exposure remain unknown. Indeed, some recent reports suggest the use of TCS as a repositioned drug for cancer treatment and cutaneous leishmaniasis. In this scenario it is necessary to investigate the advantages and disadvantages of TCS, to understand whether its use is advisable or not. This review intends to highlight the pros and cons that are associated with the use of TCS in humans.

Moving beyond the Tip of the Iceberg: DJ-1 Implications in Cancer Metabolism.

DJ-1, also called Parkinson's protein 7 (PARK7), is ubiquitously expressed and plays multiple actions in different physiological and, especially, pathophysiological processes, as evidenced by its identification in neurodegenerative diseases and its high expression in different types of cancer. To date, the exact activity of DJ-1 in carcinogenesis has not been fully elucidated, however several recent studies disclosed its involvement in regulating fundamental pathways involved in cancer onset, development, and metastatization. At this purpose, we have dissected the role of DJ-1 in maintaining the transformed phenotype, survival, drug resistance, metastasis formation, and differentiation in cancer cells. Moreover, we have discussed the role of DJ-1 in controlling the redox status in cancer cells, along with the ability to attenuate reactive oxygen species (ROS)-dependent cell death, as well as to mediate ferropotosis. Finally, a mention to the development of therapeutic strategies targeting DJ-1 has been done. We have reported the most recent studies, aiming to shed light on the role played by DJ-1 in different cancer aspects and create the foundation for moving beyond the tip of the iceberg.

Novel Au Carbene Complexes as Promising Multi-Target Agents in Breast Cancer Treatment.

Over the past decade, metal complexes based on N-heterocyclic carbenes (NHCs) have attracted great attention due to their wide and exciting applications in material sciences and medicinal chemistry. In particular, the gold-based complexes are the focus of research efforts for the development of new anticancer compounds. Literature data and recent results, obtained by our research group, reported the design, the synthesis and the good anticancer activity of some silver and gold complexes with NHC ligands. In particular, some of these complexes were active towards some breast cancer cell lines. Considering this evidence, here we report some new Au-NHC complexes prepared in order to improve solubility and biological activity. Among them, the compounds 1 and 6 showed an interesting anticancer activity towards the breast cancer MDA-MB-231 and MCF-7 cell lines, respectively. In addition, in vitro and in silico studies demonstrated that they were able to inhibit the activity of the human topoisomerases I and II and the actin polymerization reaction. Moreover, a downregulation of vimentin expression and a reduced translocation of NF-kB into the nucleus was observed. The interference with these vital cell structures induced breast cancer cells' death by triggering the extrinsic apoptotic pathway.

Multidrug Resistance (MDR): A Widespread Phenomenon in Pharmacological Therapies.

Multidrug resistance is a leading concern in public health. It describes a complex phenotype whose predominant feature is resistance to a wide range of structurally unrelated cytotoxic compounds, many of which are anticancer agents. Multidrug resistance may be also related to antimicrobial drugs, and is known to be one of the most serious global public health threats of this century. Indeed, this phenomenon has increased both mortality and morbidity as a consequence of treatment failures and its incidence in healthcare costs. The large amounts of antibiotics used in human therapies, as well as for farm animals and even for fishes in aquaculture, resulted in the selection of pathogenic bacteria resistant to multiple drugs. It is not negligible that the ongoing COVID-19 pandemic may further contribute to antimicrobial resistance. In this paper, multidrug resistance and antimicrobial resistance are underlined, focusing on the therapeutic options to overcome these obstacles in drug treatments. Lastly, some recent studies on nanodrug delivery systems have been reviewed since they may represent a significant approach for overcoming resistance.