Unveiling Histone Proteoforms using 2D-TAU Gel Electrophoresis.

Histones undergo various post-translational modifications (PTMs) such as methylation, acetylation, phosphorylation, acylation, and ubiquitination, which control nucleosome dynamics and determine cell fate. The nucleosome, which is the functional unit of chromatin, comprises DNA, four pairs of histones (H3, H4, H2A, and H2B) making up the globular core, and the linker histone H1, which stabilizes the chromatin structure. The amino (N)-terminal tails of the histones protrude from the globular core domains and undergo distinct PTMs that influence the chromatin landscape. Some evidence suggests that histone PTM homeostasis is crucial for preserving all physiological activities. The deregulation of histone PTMs is the primary cause of abnormal cellular proliferation, invasion, and metastasis. Therefore, developing methods for characterizing histone PTMs is crucial. Here, we describe an effective technique for isolating and analyzing histone isoforms. The method, based on the combination of two orthogonal separations, allows the enrichment of histone isoforms and the following mass spectrometry identification. The technique, originally described by Shechter et al., combines acid-urea polyacrylamide gels (TAU-GEL), which can separate basic histone proteins based on size and charge, and Sodium dodecyl sulfate-polyacrylamide gels (SDS-PAGE), which can separate proteins by molecular weight. The result is a two-dimensional map of histone isoforms, suitable for in-gel digestion followed by mass spectrometry identification and western blot analysis. The result is a two-dimensional map of histone isoforms, suitable for both in-gel digestion followed by mass spectrometry identification and western blot analysis. This proteomic approach is a robust method that allows the enrichment of a single histone isoform and the characterization of new histone PTMs.

New Therapies and Strategies to Curb HIV Infections with a Focus on Macrophages and Reservoirs.

More than 80 million people worldwide have been infected with the human immunodeficiency virus (HIV). There are now approximately 39 million individuals living with HIV/acquired immunodeficiency syndrome (AIDS). Although treatments against HIV infection are available, AIDS remains a serious disease. Combination antiretroviral therapy (cART), also known as highly active antiretroviral therapy (HAART), consists of treatment with a combination of several antiretroviral drugs that block multiple stages in the virus replication cycle. However, the increasing usage of cART is inevitably associated with the emergence of HIV drug resistance. In addition, the development of persistent cellular reservoirs of latent HIV is a critical obstacle to viral eradication since viral rebound takes place once anti-retroviral therapy (ART) is interrupted. Thus, several efforts are being applied to new generations of drugs, vaccines and new types of cART. In this review, we summarize the antiviral therapies used for the treatment of HIV/AIDS, both as individual agents and as combination therapies, and highlight the role of both macrophages and HIV cellular reservoirs and the most recent clinical studies related to this disease.

Aloe vera-An Extensive Review Focused on Recent Studies.

Since ancient times, Aloe vera L. (AV) has attracted scientific interest because of its multiple cosmetic and medicinal properties, attributable to compounds present in leaves and other parts of the plant. The collected literature data show that AV and its products have a beneficial influence on human health, both by topical and oral use, as juice or an extract. Several scientific studies demonstrated the numerous biological activities of AV, including, for instance, antiviral, antimicrobial, antitumor, and antifungal. Moreover, its important antidepressant activity in relation to several diseases, including skin disorders (psoriasis, acne, and so on) and prediabetes, is a growing field of research. This comprehensive review intends to present the most significant and recent studies regarding the plethora of AV's biological activities and an in-depth analysis exploring the component/s responsible for them. Moreover, its morphology and chemical composition are described, along with some studies regarding the single components of AV available in commerce. Finally, valorization studies and a discussion about the metabolism and toxicological aspects of this "Wonder Plant" are reported.

Phthalazine Sulfonamide Derivatives as Carbonic Anhydrase Inhibitors. Synthesis, Biological and in silico Evaluation.

Carbonic Anhydrases (CAs) are a large family of zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide involved in several biological processes. They show a wide diversity in tissue distribution and their subcellular localization. Twenty-two novel phthalazine derivatives were designed, synthesized, and evaluated against four human isoforms: hCA I, hCA II, hCA IX, and hCA XII. Compounds appeared to be very active mostly against hCA IX (7) and hCA I (6) isoforms being more potent than reference drug acetazolamide (AAZ). Some compounds appeared to be very selective with a selectivity index up to 13.8. Furthermore, docking was performed for some of these compounds on all isoforms to understand the possible interactions with the active site. Additionally, the most active compounds against hCA IX were subjected to cell viability assay. The anticancer activity of the compounds (3 a-d, 5 d, 5 i, and 5 m) was investigated using two human breast cancer cell lines, i. e. MCF-7 and MDA-MB-231 cells, and the normal counterpart, namely MCF10-A cells.

Phytochemicals Involved in Mitigating Silent Toxicity Induced by Heavy Metals.

Heavy metals (HMs) are natural elements present in the Earth's crust, characterised by a high atomic mass and a density more than five times higher than water. Despite their origin from natural sources, extensive usage and processing of raw materials and their presence as silent poisons in our daily products and diets have drastically altered their biochemical balance, making them a threat to the environment and human health. Particularly, the food chain polluted with toxic metals represents a crucial route of human exposure. Therefore, the impact of HMs on human health has become a matter of concern because of the severe chronic effects induced by their excessive levels in the human body. Chelation therapy is an approved valid treatment for HM poisoning; however, despite the efficacy demonstrated by chelating agents, various dramatic side effects may occur. Numerous data demonstrate that dietary components and phytoantioxidants play a significant role in preventing or reducing the damage induced by HMs. This review summarises the role of various phytochemicals, plant and herbal extracts or probiotics in promoting human health by mitigating the toxic effects of different HMs.

Silver and Gold Complexes with NHC-Ligands Derived from Caffeine: Catalytic and Pharmacological Activity.

N-heterocyclic carbene (NHC) silver(I) and gold(I) complexes have found different applications in various research fields, as in medicinal chemistry for their antiproliferative, anticancer, and antibacterial activity, and in chemistry as innovative and effective catalysts. The possibility of modulating the physicochemical properties, by acting on their ligands and substituents, makes them versatile tools for the development of novel metal-based compounds, mostly as anticancer compounds. As it is known, chemotherapy is commonly adopted for the clinical treatment of different cancers, even though its efficacy is hampered by several factors. Thus, the development of more effective and less toxic drugs is still an urgent need. Herein, we reported the synthesis and characterization of new silver(I) and gold(I) complexes stabilized by caffeine-derived NHC ligands, together with their biological and catalytic activities. Our data highlight the interesting properties of this series as effective catalysts in A3-coupling and hydroamination reactions and as promising anticancer, anti-inflammatory, and antioxidant agents. The ability of these complexes in regulating different pathological aspects, and often co-promoting causes, of cancer makes them ideal leads to be further structurally functionalized and investigated.

The Ongoing Impact of COVID-19 on Pediatric Obesity.

In the developed world, pediatric obesity (PO) has been a major health concern since the last century, and this condition may lead to detrimental life-long physical and mental comorbidities. Currently, its prevalence has increased in low- and middle-income countries and in many high-income countries. Thus, the provision of effective and tailored care for children and their families has become vital. The social consequences of the COVID-19 pandemic are known everywhere, and among these, it has been argued that the COVID-19 pandemic has had a major impact on PO. Overall, the growth of PO over the last decade has been enhanced by the pandemic. During the COVID-19 pandemic, children, adolescents and young adults gained weight as the pediatric population dealt with sedentary lifestyles and changes in food habits. In this review, we want to highlight the impact that the COVID-19 pandemic had on PO.

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 wellknown 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.

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.

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.

Benzothiazole-Phthalimide Hybrids as Anti-Breast Cancer and Antimicrobial Agents.

The benzothiazole nucleus is a major heterocyclic scaffold whose therapeutic potential has been thoroughly explored due to its structural simplicity and ease of synthesis. In fact, several benzothiazole derivatives have been synthesized over time, demonstrating numerous pharmacological properties such as anticancer, antimicrobial, anti-inflammatory, and antioxidant activities. Herein, we propose a new series of benzothiazole-phthalimide hybrids obtained by linking the phthalimide moiety to differently substituted benzothiazole nuclei through the N atom. These compounds have been screened for their anticancer properties against two human breast cancer cell lines. Furthermore, we delved into the mechanism of action of the most active hybrid, compound 3h, by assessing its capability to damage the nuclear DNA, trigger the apoptotic process in the high metastatic MDA-MB-231 cells, and prevent cellular migration. Moreover, in view of the documented antimicrobial activities of the two scaffolds involved, we explored the antibacterial and antifungal effects of the studied compounds by means of the broth microdilution method. Among the studied compounds, 3h showed the highest antimicrobial activity, both against gram-positive and gram-negative bacterial strains belonging to the ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) and against fungal strains of the Candida species with MICs values ranging from 16 to 32 µg/mL.

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.

Oil Extraction from Hemp Plant as a Potential Source of Cannabidiol for Healthy Protein Foods.

In recent years, the increasing demand for alternative foods has shifted research toward new sources enriched with nutraceutical molecules. It is well known that many diseases are caused by oxidative stress; thus, the supplementation of antioxidants has been proposed to reduce it. Cannabis sativa L. is an interesting species that could provide an alternative source of antioxidants. This work aimed to investigate the possibility of optimizing the yield of cannabidiol (CBD) and recovering it from residual biomass (stalks), valorizing the residual biomass, and using this for protein bar preparation. Different extraction methods were used, and High-Pressure Liquid Chromatography (HPLC) analysis was used to analyze the extracts. Antioxidant power was investigated using the 2,2-Diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) assays. The best results in terms of CBD yield were obtained via dynamic maceration after decarboxylation with a quantity of 26.7 ± 2 mgCBD/graw material from inflorescences. The extract also shows good antioxidant power with an IC50 value of 38.1 ± 1.1 µg/mL measured using the DPPH assay. The CBD extract was added to the hemp oil to obtain dough for protein bars. The doughs were studied by taking rheological and technological measurements, and it was found that the protein bars could provide an excellent means for the consumption of products enriched with antioxidants because their CBD anti-inflammatory activity is preserved after cooking.

Antibiotic-Resistant ESKAPE Pathogens and COVID-19: The Pandemic beyond the Pandemic.

Antibacterial resistance is a renewed public health plague in modern times, and the COVID-19 pandemic has rekindled this problem. Changes in antibiotic prescribing behavior, misinformation, financial hardship, environmental impact, and governance gaps have generally enhanced the misuse and improper access to antibiotics during the COVID-19 pandemic. These determinants, intersected with antibacterial resistance in the current pandemic, may amplify the potential for a future antibacterial resistance pandemic. The occurrence of infections with multidrug-resistant (MDR), extensively drug-resistant (XDR), difficult-to-treat drug-resistant (DTR), carbapenem-resistant (CR), and pan-drug-resistant (PDR) bacteria is still increasing. The aim of this review is to highlight the state of the art of antibacterial resistance worldwide, focusing on the most important pathogens, namely Enterobacterales, Acinetobacter baumannii, and Klebsiella pneumoniae, and their resistance to the most common antibiotics.

Development of 1-(2-aminophenyl)pyrrole-based amides acting as human topoisomerase I inhibitors.

Topoisomerases are ubiquitous enzymes in the human body, particularly involved in cancer development and progression. Topoisomerase I (topoI) performs DNA relaxation reactions by "controlled rotation" rather than by "strand passage." The inhibition of topoI has become a useful strategy to control cancer cell proliferation. Nowadays, different compounds have undergone clinical trials, but the search for new molecular entities is necessary and benefits from medicinal chemistry efforts. Pyrrole-based compounds emerged as promising antiproliferative agents, with particular interest in breast cancer therapy and topoI inhibition. Starting from these observations and based on the scaffold-hopping approach, we developed a small library of 1-(2-aminophenyl)pyrrole-based amides (7a-f) as new anticancer agents. Tested on a panel of cancer cell lines, 7a-f displayed the most interesting profile in MDA-MB-231 cells, where the most active compounds, 7d-f, were able to induce death by apoptosis. Direct enzymatic assays and docking simulations on the topoI active site (PDB: 1A35) revealed the inhibitory activity and potential binding site for the newly developed 1-(2-aminophenyl)pyrrole-based amides.

Novel Thiazolidine-2,4-dione-trimethoxybenzene-thiazole Hybrids as Human Topoisomerases Inhibitors.

Cancer is a complex and heterogeneous disease and is still one of the leading causes of morbidity and mortality worldwide, mostly as the population ages. Despite the encouraging advances made over the years in chemotherapy, the development of new compounds for cancer treatments is an urgent priority. In recent years, the design and chemical synthesis of several innovative hybrid molecules, which bring different pharmacophores on the same scaffold, have attracted the interest of many researchers. Following this strategy, we designed and synthetized a series of new hybrid compounds that contain three pharmacophores, namely trimethoxybenzene, thiazolidinedione and thiazole, and tested their anticancer properties on two breast cancer (MCF-7 and MDA-MB-231) cell lines and one melanoma (A2058) cell line. The most active compounds were particularly effective against the MCF-7 cells and did not affect the viability of the normal MCF-10A cells. Docking simulations indicated the human Topoisomerases I and II (hTopos I and II) as possible targets of these compounds, the inhibitory activity of which was demonstrated by the mean of direct enzymatic assays. Particularly, compound 7e was proved to inhibit both the hTopo I and II, whereas compounds 7c,d blocked only the hTopo II. Finally, compound 7e was responsible for MCF-7 cell death by apoptosis. The reported results are promising for the further design and synthesis of other analogues potentially active as anticancer tools.

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.