Steroidal epoxides as anticancer agents in lung, prostate and breast cancers: The case of 1,2-epoxysteroids.

Cancer continues to be a serious threat to human health worldwide. Lung, prostate and triple-negative breast cancers are amongst the most incident and deadliest cancers. Steroidal compounds are one of the most diversified therapeutic classes of compounds and they were proven to be efficient against several types of cancer. The epoxide function has been frequently associated with anticancer activity, particularly the 1,2-epoxide function. For this reason, three 1,2-epoxysteroid derivatives previously synthesised (EP1, EP2 and EP3) and one synthesised for the first time (oxysteride) were evaluated against H1299 (lung), PC3 (prostate) and HCC1806 (triple-negative breast) cancer cell lines. A human non-tumour cell line, MRC-5 (normal lung cell line) was also used. EP2 was the most active compound in all cell lines with IC50 values of 2.50, 3.67 and 1.95 µM, followed by EP3 with IC50 values of 12.65, 15.10 and 14.16 µM in H1299, PC3 and HCC1806 cells, respectively. Additional studies demonstrated that EP2 and EP3 induced cell death by apoptosis at lower doses and apoptosis/necrosis at higher doses, proving that their effects were dose-dependent. Both compounds also exerted their cytotoxicity by ROS production and by inducing double-strand breaks. Furthermore, EP2 and EP3 proved to be much less toxic against a normal lung cell line, MRC5, indicating that both compounds might be selective, and they also demonstrated suitable in silico ADME and toxicity parameters. Finally, none of the compounds induced haemoglobin release. Altogether, these results point out the extreme relevance of both compounds, especially EP2, in the potential treatment of these types of cancer.

The Effect of Phenolic-Rich Extracts of Rubus fruticosus, R. ulmifolius and Morus nigra on Oxidative Stress and Caco-2 Inhibition Growth.

Currently, a clear interest has been given to berries due to their richness in active metabolites, including anthocyanins and non-coloured phenolics. Therefore, the main aim of the present work is to investigate the phenolic profile, antioxidant abilities, and antiproliferative effects on normal human dermal fibroblasts (NHDF) and human colon carcinoma cell line (Caco-2) cells of phenolic-rich extracts from three red fruits highly appreciated by consumers: two species of blackberries (Rubus fruticosus and Rubus ulmifolius) and one species of mulberry (Morus nigra). A total of 19 different phenolics were identified and quantified by HPLC-DAD-ESI/MSn and HPLC-DAD, respectively. Focusing on the biological potential of the phenolic-rich extracts, all of them revealed notable scavenging abilities. Concerning the antiproliferative properties, R. fruticosus presented a cytotoxic selectivity for Caco-2 cells compared to NHDF cells. To deeper explore the biological potential, combinations with positive controls (ascorbic acid and 5-fluorouracil) were also conducted. Finally, the obtained data are another piece of evidence that the combination of phenolic-rich extracts from natural plants with positive controls may reduce clinical therapy costs and the possible toxicity of chemical drugs.

Potential Role of Dietary Phenolic Compounds in the Prevention and Treatment of Rheumatoid Arthritis: Current Reports.

Rheumatoid arthritis (RA) is a complex illness with both hereditary and environmental components. Globally, in 2019, 18 million people had RA. RA is characterized by persistent inflammation of the synovial membrane that lines the joints, cartilage loss, and bone erosion. Phenolic molecules are the most prevalent secondary metabolites in plants, with a diverse spectrum of biological actions that benefit functional meals and nutraceuticals. These compounds have received a lot of attention recently because they have antioxidant, anti-inflammatory, immunomodulatory, and anti-rheumatoid activity by modulating tumor necrosis factor, mitogen-activated protein kinase, nuclear factor kappa-light-chain-enhancer of activated B cells, and c-Jun N-terminal kinases, as well as other preventative properties. This article discusses dietary polyphenols, their pharmacological properties, and innovative delivery technologies for the treatment of RA, with a focus on their possible biological activities. Nonetheless, commercialization of polyphenols may be achievable only after confirming their safety profile and completing successful clinical trials.

Antioxidant activity of the main phenolics found in red fruits: An in vitro and in silico study.

The current study analysed the antioxidant capacity of the main phenolics found in red fruits. In total, there were analysed the antioxidant activity against 1,1-diphenyl-2-picrylhydrazyl radical, nitric oxide and superoxide radicals (DPPH, NO and O2-, respectively) of 23 phenolics. Regarding DPPH, anthocyanins, (-)-epicatechin and kaempferol 3-O-rutinoside were the most active, while isorhamnetin 3-O-glucoside was the least active. Anthocyanins, (-)-epicatechin, quercetin 3-O-glucoside and caffeic acid showed the strongest potential against NO, while ρ-hydroxybenzoic acid was the less efficient. Regarding the O2- assay, quercetin aglycone and their derivatives were the best ones, while cyanidin aglycone did not show any potential to quench this radical. To deeper explore the biological potential of the most promising compounds, docking molecular and ADME studies were also done. The obtained data is another support regarding the biological potential of phenolics and might be useful in encouraging their use and incorporation in new products.

Diversity of Culture Microorganisms from Portuguese Sweet Cherries.

Consumers today seek safe functional foods with proven health-promoting properties. Current evidence shows that a healthy diet can effectively alleviate oxidative stress levels and reduce inflammatory markers, thereby preventing the occurrence of many types of cancer, hypertension, and cardiovascular and neurological pathologies. Nevertheless, as fruits and vegetables are mainly consumed fresh, they can serve as vectors for the transmission of pathogenic microorganisms associated with various disease outbreaks. As a result, there has been a surge in interest in the microbiome of fruits and vegetables. Therefore, given the growing interest in sweet cherries, and since their microbial communities have been largely ignored, the primary purpose of this study is to investigate their culturome at various maturity stages for the first time. A total of 55 microorganisms were isolated from sweet cherry fruit, comprising 23 bacteria and 32 fungi species. Subsequently, the selected isolates were molecularly identified by amplifying the 16S rRNA gene and ITS region. Furthermore, it was observed that the communities became more diverse as the fruit matured. The most abundant taxa included Pseudomonas and Ralstonia among the bacteria, and Metschnikowia, Aureobasidium, and Hanseniaspora among the fungi.

Overview of Caffeine Effects on Human Health and Emerging Delivery Strategies.

Caffeine is a naturally occurring alkaloid found in various plants. It acts as a stimulant, antioxidant, anti-inflammatory, and even an aid in pain management, and is found in several over-the-counter medications. This naturally derived bioactive compound is the best-known ingredient in coffee and other beverages, such as tea, soft drinks, and energy drinks, and is widely consumed worldwide. Therefore, it is extremely important to research the effects of this substance on the human body. With this in mind, caffeine and its derivatives have been extensively studied to evaluate its ability to prevent diseases and exert anti-aging and neuroprotective effects. This review is intended to provide an overview of caffeine's effects on cancer and cardiovascular, immunological, inflammatory, and neurological diseases, among others. The heavily researched area of caffeine in sports will also be discussed. Finally, recent advances in the development of novel nanocarrier-based formulations, to enhance the bioavailability of caffeine and its beneficial effects will be discussed.

Blackberries and Mulberries: Berries with Significant Health-Promoting Properties.

Blackberries and mulberries are small and perishable fruits that provide significant health benefits when consumed. In reality, both are rich in phytochemicals, such as phenolics and volatile compounds, and micronutrients, such as vitamins. All the compounds are well-known thanks to their medicinal and pharmacological properties, namely antioxidant, anti-inflammatory, anti-cancer, antiviral, and cardiovascular properties. Nevertheless, variables such as genotype, production conditions, fruit ripening stage, harvesting time, post-harvest storage, and climate conditions influence their nutritional composition and economic value. Given these facts, the current review focuses on the nutritional and chemical composition, as well as the health benefits, of two blackberry species (Rubus fruticosus L., and Rubus ulmifolius Schott) and one mulberry species (Morus nigra L.).

New ruthenium(II) complexes with cyclic thio- and semicarbazone: evaluation of cytotoxicity and effects on cell migration and apoptosis of lung cancer cells.

We describe the synthesis, physicochemical characterization, and in vitro antitumor assays of four novel analogous ruthenium(II) complexes with general formula cis-[RuII(N-L)(P-P)2]PF6, where P-P = bis(diphenylphosphine)methane (dppm, in complexes 1 and 2) or bis(diphenylphosphine)ethane (dppe, in complexes 3 and 4) and N-L = 5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazine-3-thione (Btsc, in complexes 1 and 3) or 5,6-diphenyltriazine-3-one (Bsc, in complexes 2 and 4). The data were consistent with cis arrangement of the biphosphine ligands. For the Btsc and Bsc ligands, the data pointed to monoanionic bidentate coordination to ruthenium(II) through N,S and N,O, respectively. Single-crystal X-ray diffraction showed that complex 1 crystallized in the monoclinic system, space group P21/c. Determination of the cytotoxicity profiles of complexes 1-4 gave SI values ranging from 1.19 to 3.50 against the human lung adenocarcinoma cell line A549 and the non-tumor lung cell line MRC-5. Although the molecular docking studies suggested that the interaction between DNA and complex 4 was energetically favorable, the experimental results showed that they interacted weakly. Overall, our results demonstrated that these novel ruthenium(II) complexes have interesting in vitro antitumor potential and this study may contribute to further studies in medicinal inorganic chemistry.

Insight into the Taxonomic and Functional Diversity of Bacterial Communities Inhabiting Blueberries in Portugal.

Vaccinium myrtillus is a dwarf shrub of the Ericaceae family with a Palearctic distribution, associated with temperate and cold humid climates. It is widespread on the European continent; on the Iberian Peninsula it is located on Atlantic climate mountains and glacial relicts. In Portugal, we find scattered and interesting populations; however, the majority of them are threatened by climate change and wildfires. Given that, the objective of this study is to determine the rhizospheric and root bacterial communities of this plant in the southernmost regions, and, consequently, its potential range and ability to be used as a biofertilizer. In this work, metabarcoding of 16S rRNA gene showed that the endophytic bacterial diversity is dependent on the plant and selected by it according to the observed alpha and beta diversity. Moreover, a culturomic approach allowed 142 different strains to be isolated, some of them being putative new species. Additionally, some strains belonging to the genera Bacillus, Paenibacillus, Pseudomonas, Paraburkholderia, and Caballeronia showed significant potential to be applied as multifunctional biofertilizers since they present good plant growth-promoting (PGP) mechanisms, high colonization capacities, and an increase in vegetative parameters in blueberry and tomato plants.

Anti-Inflammatory and Antimicrobial Activities of Portuguese Prunus avium L. (Sweet Cherry) By-Products Extracts.

The bioactivity of natural by-products in food and pharmaceutical applications is the subject of numerous studies. Cherry production and processing generates large amounts of biowaste, most of which is not used. The recovery of these by-products is essential for promoting the circular economy and to improving sustainability in the food industry. In this work, we explored the anti-inflammatory and antimicrobial potential of two different extracts from stems, leaves, and flowers of Portuguese cherries. The anti-inflammatory potential was studied on lipopolysaccharide (LPS)-stimulated mouse macrophages (RAW 264.7) by evaluating the effect of by-products on cellular viability and nitric oxide (NO) production. Disc diffusion and minimum inhibitory concentration (MIC) were used to determine antimicrobial activity. The cherry by-products had no cytotoxic effect on RAW 264.7 cells, and were able to inhibit nitrite production in a dose-dependent manner. Moreover, all aqueous infusions showed good antioxidant activity against NO radicals. Moreover, leaf extracts showed the best activity against most of the strains studied. The results revealed, for the first time, interesting anti-inflammatory and antimicrobial properties of cherry by-products. This could potentially be of interest for their therapeutic use in the treatment of inflammation-related diseases or in controlling the growth of microorganisms.

Employ of Anthocyanins in Nanocarriers for Nano Delivery: In Vitro and In Vivo Experimental Approaches for Chronic Diseases.

Anthocyanins are among the best-known phenolic compounds and possess remarkable biological activities, including antioxidant, anti-inflammatory, anticancer, and antidiabetic effects. Despite their therapeutic benefits, they are not widely used as health-promoting agents due to their instability, low absorption, and, thus, low bioavailability and rapid metabolism in the human body. Recent research suggests that the application of nanotechnology could increase their solubility and/or bioavailability, and thus their biological potential. Therefore, in this review, we have provided, for the first time, a comprehensive overview of in vitro and in vivo studies on nanocarriers used as delivery systems of anthocyanins, and their aglycones, i.e., anthocyanidins alone or combined with conventional drugs in the treatment or management of chronic diseases.

SARS-CoV-2 Seroconversion in Response to Infection and Vaccination: a Time Series Local Study in Brazil.

The investigation of antibodies raised against different severe acute respiratory syndrome coronavirus (SARS-CoV-2) antigens can help to determine the extent of previous SARS-CoV-2 infections in the population and track the humoral response to vaccination. Therefore, serological surveys can provide key information to better manage the pandemic and/or to implement the most effective vaccination program. Here we describe a time series anti-nucleocapsid, anti-spike IgG serological survey analysis in the city of Matinhos, PR, Brazil during the year of 2021. Seroconversion rates to the nucleocapsid antigen were not influenced by gender or age. The serological data support that the coronavirus disease 2019 (COVID-19) infection rate is ~50% higher than official numbers. Furthermore, by applying serological data, the corrected infection fatality rate was estimated to be lower than 2.4% in contrast with the official estimative of 3.6%. The rates of IgG reactive to spike antigen resembled the curve of the fraction the population that had taken the second vaccine dose. Up to 82% of spike seroconversion was detected in the end of 2021, confirming the effectiveness of the COVID-19 vaccination program in the city. This SARS-CoV-2 serological study unraveled the SARS-CoV-2 infection rates and the response to vaccination in the city of Matinhos. IMPORTANCE The investigation of antibodies raised against SARS-CoV-2 can help to determine the extent of previous SARS-CoV-2 infections and track the humoral response to vaccination. Here we describe a time series anti-nucleocapsid, anti-spike IgG serological survey in the city of Matinhos, PR, Brazil during the year of 2021. The data depicted the progression of SARS-CoV-2 infections in the city allowing the correction of the number of citizens who experienced COVID-19 and the disease fatality rate. The seroconversion rates to the spike antigen resembled the curve of the fraction of the population that had taken the second vaccine dose, thereby confirming the effectiveness of the COVID-19 vaccination program in the city.

Cherries and Blueberries-Based Beverages: Functional Foods with Antidiabetic and Immune Booster Properties.

Nowadays, it is largely accepted that the daily intake of fruits, vegetables, herbal products and derivatives is an added value in promoting human health, given their capacity to counteract oxidative stress markers and suppress uncontrolled pro-inflammatory responses. Given that, natural-based products seem to be a promising strategy to attenuate, or even mitigate, the development of chronic diseases, such as diabetes, and to boost the immune system. Among fruits, cherries and blueberries are nutrient-dense fruits that have been a target of many studies and interest given their richness in phenolic compounds and notable biological potential. In fact, research has already demonstrated that these fruits can be considered functional foods, and hence, their use in functional beverages, whose popularity is increasing worldwide, is not surprising and seem to be a promising and useful strategy. Therefore, the present review reinforces the idea that cherries and blueberries can be incorporated into new pharmaceutical products, smart foods, functional beverages, and nutraceuticals and be effective in preventing and/or treating diseases mediated by inflammatory mediators, reactive species, and free radicals.

Effects of Functional Phenolics Dietary Supplementation on Athletes' Performance and Recovery: A Review.

In recent years, many efforts have been made to identify micronutrients or nutritional strategies capable of preventing, or at least, attenuating, exercise-induced muscle damage and oxidative stress, and improving athlete performance. The reason is that most exercises induce various changes in mitochondria and cellular cytosol that lead to the generation of reactive species and free radicals whose accumulation can be harmful to human health. Among them, supplementation with phenolic compounds seems to be a promising approach since their chemical structure, composed of catechol, pyrogallol, and methoxy groups, gives them remarkable health-promoting properties, such as the ability to suppress inflammatory processes, counteract oxidative damage, boost the immune system, and thus, reduce muscle soreness and accelerate recovery. Phenolic compounds have also already been shown to be effective in improving temporal performance and reducing psychological stress and fatigue. Therefore, the aim of this review is to summarize and discuss the current knowledge on the effects of dietary phenolics on physical performance and recovery in athletes and sports practitioners. Overall, the reports show that phenolics exert important benefits on exercise-induced muscle damage as well as play a biological/physiological role in improving physical performance.

A magnetic bead immunoassay to detect high affinity human IgG reactive to SARS-CoV-2 Spike S1 RBD produced in Escherichia coli.

Immunological assays to detect SARS-CoV-2 Spike Receptor Binding Domain (RBD) antigen seroconversion in humans are important tools to monitor the levels of protecting antibodies in the population in response to infection and/or immunization. Here we describe a simple, low cost, and high throughput Ni2+ magnetic bead immunoassay to detect human IgG reactive to Spike S1 RBD Receptor Binding Domain produced in Escherichia coli. A 6xHis-tagged Spike S1 RBD was expressed in E. coli and purified by affinity chromatography. The protein was mobilized on the surface of Ni2+ magnetic beads and used to investigate the presence of reactive IgG in the serum obtained from pre-pandemic and COVID-19 confirmed cases. The method was validated with a cohort of 290 samples and an area under the receiver operating characteristic curve of 0.94 was obtained. The method was operated with > 82% sensitivity at 98% specificity and was also able to track human IgG raised in response to vaccination with Comirnaty at > 85% sensitivity. The IgG signal obtained with the described method was well-correlated with the signal obtained when pre fusion Spike produced in HEK cell lines was used as antigen. This novel low-cost and high throughput immunoassay may act as an important tool to investigate protecting IgG antibodies against SARS-CoV-2 in the human population.

Zimbro (Juniperus communis L.) as a Promising Source of Bioactive Compounds and Biomedical Activities: A Review on Recent Trends.

Plant-derived products and their extracted compounds have been used in folk medicine since early times. Zimbro or common juniper (Juniperus communis) is traditionally used to treat renal suppression, acute and chronic cystitis, bladder catarrh, albuminuria, leucorrhea, and amenorrhea. These uses are mainly attributed to its bioactive composition, which is very rich in phenolics, terpenoids, organic acids, alkaloids, and volatile compounds. In the last few years, several studies have analyzed the huge potential of this evergreen shrub, describing a wide range of activities with relevance in different biomedical discipline areas, namely antimicrobial potential against human pathogens and foodborne microorganisms, notorious antioxidant and anti-inflammatory activities, antidiabetic, antihypercholesterolemic and antihyperlipidemic effects, and neuroprotective action, as well as antiproliferative ability against cancer cells and the ability to activate inductive hepato-, renal- and gastroprotective mechanisms. Owing to these promising activities, extracts and bioactive compounds of juniper could be useful for the development of new pharmacological applications in the treatment of several acute and chronic human diseases.

Mineral Content and Volatile Profiling of Prunus avium L. (Sweet Cherry) By-Products from Fundão Region (Portugal).

Large amounts of Prunus avium L. by-products result from sweet cherry production and processing. This work aimed to evaluate the mineral content and volatile profiling of the cherry stems, leaves, and flowers of the Saco cultivar collected from the Fundão region (Portugal). A total of 18 minerals were determined by ICP-MS, namely 8 essential and 10 non-essential elements. Phosphorus (P) was the most abundant mineral, while lithium (Li) was detected in trace amounts. Three different preparations were used in this work to determine volatiles: hydroethanolic extracts, crude extracts, and aqueous infusions. A total of 117 volatile compounds were identified using HS-SPME/GC-MS, distributed among different chemical classes: 31 aldehydes, 14 alcohols, 16 ketones, 30 esters, 4 acids, 4 monoterpenes, 3 norisoprenoids, 4 hydrocarbons, 7 heterocyclics, 1 lactone, 1 phenol, and 2 phenylpropenes. Benzaldehyde, 4-methyl-benzaldehyde, hexanal, lilac aldehyde, and 6-methyl-5-hepten-2-one were the major volatile compounds. Differences in the types of volatiles and their respective amounts in the different extracts were found. This is the first study that describes the mineral and volatile composition of Portuguese sweet cherry by-products, demonstrating that they could have great potential as nutraceutical ingredients and natural flavoring agents to be used in the pharmaceutical, cosmetic, and food industries.

Reduced Levels of Circulating Endothelial Cells and Endothelial Progenitor Cells in Patients with Heart Failure with Reduced Ejection Fraction.

BACKGROUND: Endothelial dysfunction has been suggested as a potential mechanism contributing to the development and progression of heart failure (HF). Levels of circulating endothelial cells (CECs), endothelial progenitor cells (EPCs), and hematopoietic stem and progenitor cells (HSPCs) have been recognized as useful markers of vascular damage and endothelial repair in response to tissue injury. AIMS: To evaluate the circulating levels of EPCs, CECs, and HSPCs among patients with HF with reduced ejection fraction (HFrEF). METHODS: In 82 individuals (42 patients with HFrEF and 42 age-matched subjects without established cardiovascular disease), peripheral blood was drawn and levels of EPCs, CECs, and HSPCs were quantified by flow cytometry. RESULTS: Patients with HFrEF showed lower levels of circulating EPCs (5.28 × 10-3 ± 6.83 × 10-4% vs. 7.76 × 10-3 ± 4.91 × 10-4%, p ≤0.001) and CECs (5.11 × 10-3 ± 7.87 × 10-4% vs. 6.51 × 10-3 ± 5.21 × 10-4%, p = 0.005) when compared to the age-matched group. Circulating levels of HSPCs were not significantly different between groups (p = 0.590). Additionally, the number of EPCs and CECs was significantly higher in HFrEF patients with overweight/obesity (n = 24) compared to patients with normal weight (n = 17). CONCLUSION: Circulating levels of EPCs and CECs were significantly decreased in patients with HFrEF in comparison to age-matched subjects without established cardiovascular disease, suggesting that the levels of CECs and EPCs may be potential biomarkers of the cellular response to vascular injury in patients with HFrEF.

Anti-Inflammatory and Antiproliferative Properties of Sweet Cherry Phenolic-Rich Extracts.

Cherries have largely been investigated due to their high content in phenolics in order to fully explore their health-promoting properties. Therefore, this work aimed to assess, for the first time, the anti-inflammatory potential of phenolic-targeted fractions of the Saco cherry, using RAW 264.7 macrophages stimulated with lipopolysaccharide. Additionally, the cytotoxic effects on gastric adenocarcinoma (AGS), neuroblastoma (SH-SY5Y) and normal human dermal fibroblast (NHDF) cells were evaluated, as well as the ability to protect these cellular models against induced oxidative stress. The obtained data revealed that cherry fractions can interfere with cellular nitric oxide (NO) levels by capturing NO radicals and decreasing inducible nitric oxide synthase and cyclooxygenase-2 expression. Furthermore, it was observed that all cherry fractions exhibited dose-dependent cytotoxicity against AGS cells, presenting cytotoxic selectivity for these cancer cells when compared to SH-SY5Y and NHDF cells. Regarding their capacity to protect cancer cells against oxidative injury, in most assays, the total cherry extract was the most effective. Overall, this study reinforces the idea that sweet cherries can be incorporated into new pharmaceutical products, smart foods and nutraceuticals.

Essential and non-essential elements, and volatile organic compounds for the discrimination of twenty-three sweet cherry cultivars from Fundão, Portugal.

The mineral contents and volatile profiles of 23 sweet cherry cultivars were determined. A total of 27 minerals were determined by ICP-MS and flame atomic absorption spectrometry, including 12 essential and 15 non-essential elements. K was the most abundant in all cultivars, while Tl was the one found in the smallest amounts. A total of 66 volatiles were identified using SPME/GC-MS, including 16 aldehydes, 23 alcohols, 6 ketones, 6 esters, 8 monoterpenes, 3 norisoprenoids, 2 hydrocarbons and 2 acids. Benzaldehyde, hexanal, nonanal, benzyl alcohol, (E)-2-hexen-1-ol, 1-hexanol, (Z)-2-hexen-1-ol, 2-ethyl-1-hexanol, linalool, α-terpineol and α-ionone were the major ones. Qualitative and quantitative differences were observed among the cultivars, which influenced nutritional potential and aroma. Cherries from Fundão region contain high concentrations of phytochemicals and nutritional components. 4-84, Burlat and Celeste might be considered some of the most interesting cultivars, since they are rich in essential minerals and present high diversity in volatiles.