Hybrids of 4-hydroxy derivatives of goniothalamin and piplartine bearing a diester or a 1,2,3-triazole linker as antiproliferative agents.

A library of nine hybrids of 4-hydroxygoniothalamin (2), 4-hydroxypiplartine (4), monastrol (5) and oxo-monastrol (6) was prepared via a modular synthetic route with a diester or a 1,2,3-triazole as linkers. The compounds were assayed against a panel of human cancer cell lines, including MCF-7 (breast adenocarcinoma), HeLa (cervical adenocarcinoma), Caco-2 (colorectal adenocarcinoma) and PC3 (prostate adenocarcinoma), as well as against normal breast (MCF10A) and prostate (PNT2) cells. In general, hybrids with an ester linker containing 4-hydroxypiplartine (4) were more potent than the corresponding hybrids with 4-hydroxygoniothalamin (2). On the other hand, compounds presenting the 1,2,3-triazole linker displayed enhanced cytotoxicity and selectivity when compared to their corresponding hybrids with the diester linker. The 4-hydroxypiplartine-based hybrids 12 and 22 displayed high cytotoxicity (IC50 values below 10 µM) against all cancer cells studied, especially in MCF-7 cells with IC50 values of 1.7 ± 0.1 and 1.6 ± 0.9 µM, respectively. Furthermore, the 4-hydroxygoniothalamin-monastrol hybrid (compound 21) and the 4-hydroxypiplartine-oxo-monastrol hybrid (compound 25), both bearing a 1,2,3-triazole linker, displayed high selectivity and potency towards breast cancer cell line (MCF-7 vs. MCF10 cells, selectivity index = 15.8 and 7.1, respectively), while the 4-hydroxypiplartine -4-hydroxymethylgoniothalamin hybrid with a diester linker (compound 33) showed high selectivity towards melanoma cancer cells (selectivity index = 9.6). Antiproliferative and pro-apoptotic potential of compounds 12 and 22 against MCF-7 cancer cells were further investigated. Cell cycle studies revealed increased G2/M population in MCF-7 cultures as well as reduced G0/G1 population compared to the control groups indicating cell cycle arrest in G2/M phase. In addition, the frequency of positive cells for annexin V was higher in treated samples suggesting that compounds 12 and 22 induce apoptosis in estrogen-positive MCF-7 cells.

COVID-19 pandemic outbreak: the Brazilian reality from the first case to the collapse of health services.

Coronavirus is associated with several infectious diseases that cause outbreaks in humans, such as SARS in 2002-2003 and MERS in 2012. In December 2019, COVID-19, promoted by the SARS-CoV-2 virus, was first reported in Wuhan (China) as a new coronavirus disease. This outbreak quickly reached a pandemic status, affecting at least 185 countries and territories to date on all continents. The first case of COVID-19 reported in São Paulo city (Brazil) occurred in February 26th. Days later, 182 suspected cases in 16 states were being monitored. In May 30th, 514,849 cases and 29,314 deaths were confirmed in Brazil comprising all 26 states and Federal District. The primary measure in order to contain the spread of SARS-CoV-2 involved social isolation. At that time there were not enough diagnostic tests to identify infected individuals and data were strongly associated with sub notifications. Nevertheless, the effectiveness of this measure largely depends on the individual's social responsibility. This measure has a severe economic and social impact, as in other countries. In this review, we present an overview and scientific perspectives of the evolution of COVID-19 from Brazilian databases in which climate and economic situations differ from China, European countries, and the USA.

YM155 induces apoptosis in p53-deficient T-acute lymphoblastic leukemia cells independent of survivin inhibition.

T-acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer that arises from the malignant transformation of T-cell progenitors. Despite the significant progress in current treatment, challenges remain the lifelong morbidity after current chemotherapy regimens and postrelapse survival. In addition, patients with T-ALL have inferior outcomes compared with those with B-cell precursor; consequently, novel therapeutic approaches are still necessary to improve the outcome in this cohort. YM155 is an imidazolium derivative originally discovered as a suppressant of survivin expression. It has been reported that YM155 has potent antiproliferative activity on a variety of human cancer cell lines; however, its effects in T-ALL cells have been underexplored. The aim of the present study was to examine the effects of YM155 on p53-deficient T-ALL cell lines, JURKAT and CCRF-CEM. Resazurin dye was used to evaluate cell viability. Colony formation was observed in MethoCult methylcellulose medium. Apoptotic cells were detected by flow cytometry (annexin V labeling and TUNEL assay). Cell cycle analysis was carried out by DNA quantification in flow cytometry. DNA damage was assessed using a comet assay and the survivin expression profile was evaluated by real-time PCR and immunoblotting. YM155 treatment decreased cell viability and clonogenicity capacity of T-ALL cells, increased the apoptosis index and DNA damage, and altered the cell cycle dynamic, independent of survivin inhibition. Taken together, the data reinforce that YM155 may be useful as a therapeutic possibility to combat leukemia.

7-Epiclusianone, a Benzophenone Extracted from Garcinia brasiliensis (Clusiaceae), Induces Cell Cycle Arrest in G1/S Transition in A549 Cells.

Lung cancer is the leading cause of cancer deaths in the world. Disease stage is the most relevant factor influencing mortality. Unfortunately, most patients are still diagnosed at an advanced stage and their five-year survival rate is only 4%. Thus, it is relevant to identify novel drugs that can improve the treatment options for lung cancer. Natural products have been an important source for the discovery of new compounds with pharmacological potential including antineoplastic agents. We have previously isolated a prenylated benzophenone (7-epiclusianone) from Garcinia brasiliensis (Clusiaceae) that has several biological properties including antiproliferative activity against cancer cell lines. In continuation with our studies, the present work aimed to investigate the mechanisms involved with antiproliferative activity of 7-epiclusianone in A549 cells. Our data showed that 7-epiclusianone reduced the viability of A549 cells in a concentration-dependent manner (IC50 of 16.13 ± 1.12 µM). Cells were arrested in G1/S transition and apoptosis was induced. In addition, we observed morphological changes with cytoskeleton disorganization in consequence of the treatment. Taken together, the results showed that cell cycle arrest in G1/S transition is the main mechanism involved with antiproliferative activity of 7-epiclusianone. Our results are promising and open up the prospect of using this compound in further anticancer in vivo studies.

Minimally Processed Vegetables in Brazil: An Overview of Marketing, Processing, and Microbiological Aspects.

The global demand for minimally processed vegetables (MPVs) has grown, driven by changes in the population's lifestyle. MPVs are fresh vegetables that undergo several processing steps, resulting in ready-to-eat products, providing convenience for consumers and food companies. Among the processing steps, washing-disinfection plays an important role in reducing the microbial load and eliminating pathogens that may be present. However, poor hygiene practices can jeopardize the microbiological quality and safety of these products, thereby posing potential risks to consumer health. This study provides an overview of minimally processed vegetables (MPVs), with a specific focus on the Brazilian market. It includes information on the pricing of fresh vegetables and MPVs, as well as an examination of the various processing steps involved, and the microbiological aspects associated with MPVs. Data on the occurrence of hygiene indicators and pathogenic microorganisms in these products are presented. The focus of most studies has been on the detection of Escherichia coli, Salmonella spp., and Listeria monocytogenes, with prevalence rates ranging from 0.7% to 100%, 0.6% to 26.7%, and 0.2% to 33.3%, respectively. Foodborne outbreaks associated with the consumption of fresh vegetables in Brazil between 2000 and 2021 were also addressed. Although there is no information about whether these vegetables were consumed as fresh vegetables or MPVs, these data highlight the need for control measures to guarantee products with quality and safety to consumers.

Pharmaconutrition in the Clinical Management of COVID-19: A Lack of Evidence-Based Research But Clues to Personalized Prescription.

A scientific interest has emerged to identify pharmaceutical and nutritional strategies in the clinical management of coronavirus disease 2019 (COVID-19). The purpose of this narrative review is to critically assess and discuss pharmaconutrition strategies that, secondary to accepted treatment methods, could be candidates in the current context of COVID-19. Oral medicinal doses of vitamin C (1-3 g/d) and zinc (80 mg/d elemental zinc) could be promising at the first signs and symptoms of COVID-19 as well as for general colds. In critical care situations requiring parenteral nutrition, vitamin C (3-10 g/d) and glutamine (0.3-0.5 g/kg/d) administration could be considered, whereas vitamin D3 administration (100,000 IU administered intramuscularly as a one-time dose) could possess benefits for patients with severe deficiency. Considering the presence of n-3 polyunsaturated fatty acids and arginine in immune-enhancing diets, their co-administration may also occur in clinical conditions where these formulations are recommended. However, despite the use of the aforementioned strategies in prior contexts, there is currently no evidence of the utility of any nutritional strategies in the management of SARS-CoV-2 infection and COVID-19. Nevertheless, ongoing and future clinical research is imperative to determine if any pharmaconutrition strategies can halt the progression of COVID-19.

Vinegar (acetic acid) intake on glucose metabolism: A narrative review.

Vinegar intake is considered a food item that improves blood glucose in humans. This review aimed to discuss studies that investigated the impact of vinegar intake on the glycemic profile in humans and the putative mechanistic cellular pathways in both human and animal models. A search of literature was performed on the Cochrane, MEDLINE and Web of Science databases for articles published between 1995 and 2018. There is considerable support for vinegar having a positive acute effect on blood glucose levels when combined with carbohydrate-rich meals. Conversely, there are few chronic interventions analyzing the impact of vinegar intake on blood glucose. Based on available evidence, we hypothesize three pathways by which vinegar may improve blood glucose: The inhibition of α-amylase action; increased glucose uptake; and mediation by transcription factors. When evaluating the current body of literature, daily vinegar intake in amounts of ∼10-30 mL (∼2-6 tablespoons) appear to improve the glycemic response to carbohydrate-rich meals; however, there is a paucity of studies investigating chronic effects of vinegar intake.

To what extent does cinnamon administration improve the glycemic and lipid profiles?

BACKGROUND & AIMS: Cinnamon is a condiment used in cooking and by some in large quantities as a supplement with purported hypoglycemic and lipid-lowering potential. The current literature review aims to discuss the evidence of cinnamon administration regarding its hypoglycemic and lipid-lowering effects, summarizing clinical recommendations. METHODS: Electronic databases including PubMed, Cochrane library, Science Direct and Web of Science were searched with the scientific name of the plant as well as the common name. The search for articles was based on following keywords: "cinnamon diabetes", "cinnamon diabetes type 2", "cinnamon and diabetes type 2", "Cinnamomum aromaticum", "Cinnamomum cassia", "Cinnamomum verum", "Cinnamomum zeylanicum". We carried out inclusion criteria between 2003 and 2018 focusing on human studies. RESULTS: Concerning glycemic profile, in individuals with type II diabetes mellitus the fasting blood glucose reduced from 12.9 to 52.2 mg/dL and HbA1c from 0.27 to 0.83%, whereas serum insulin decreased in few studies. Research papers ranged from 6 to 17 weeks in duration. The lipid lowering potential, in turn, is most controversial compared to anti-hyperglycemic potential. Also cinnamon administration has been claimed to reduce fat mass and raise serum antioxidants, but the studies used inaccurate methods. Two species are most investigated, C. cassia/aromaticum, and C.zeylanicum/verum. CONCLUSIONS: About 1-6 g of these cinnamon species mainly in powder seems to be an adjunct drug treatment for type 2 diabetes mellitus and other conditions of glycemic impairment. However, more controlled clinical trials are needed.

[Ru(pipe)(dppb)(bipy)]PF6: A novel ruthenium complex that effectively inhibits ERK activation and cyclin D1 expression in A549 cells.

Lung cancer is the most frequent type of cancer worldwide. In Brazil, only 14% of the patients diagnosed with lung cancer survived 5years in the last decades. Although improvements in the therapeutic approach, it is relevant to identify new chemotherapeutic agents. In this framework, ruthenium metal compounds emerge as a promising alternative to platinum-based compounds once they displayed lower cytotoxicity and more selectivity for tumor cells. The present study aimed to evaluate the antitumor potential of innovative ruthenium(II) complex, [Ru(pipe)(dppb)(bipy)]PF6 (PIPE) on A549 cells, which is derived from non-small cell lung cancer. Results demonstrated that PIPE effectively reduced the viability and proliferation rate of A549 cells. When PIPE was used at 9µM there was increase in G0/G1 cell population with concomitant reduction in frequency of cells in S-phase, indicating cell cycle arrest in G1/S transition. Antiproliferative activity of PIPE was associated to its ability of reducing cyclin D1 expression and ERK phosphorylation levels. Cytotoxic activity of PIPE on A549 cells was observed when PIPE was used at 18µM, which was associated to its ability of inducing apoptosis by intrinsic pathway. Taken together, the data demonstrated that PIPE is a promising antitumor agent and further in vivo studies should be performed.

Design, Synthesis, and Pharmacological Evaluation of Novel N-Acylhydrazone Derivatives as Potent Histone Deacetylase 6/8 Dual Inhibitors.

This manuscript describes a novel class of N-acylhydrazone (NAH) derivatives that act as histone deacetylase (HDAC) 6/8 dual inhibitors and were designed from the structure of trichostatin A (1). Para-substituted phenyl-hydroxamic acids presented a more potent inhibition of HDAC6/8 than their meta analogs. In addition, the effect of compounds (E)-4-((2-(4-(dimethylamino)benzoyl)hydrazono)methyl)-N-hydroxybenzamide (3c) and (E)-4-((2-(4-(dimethylamino)benzoyl)-2-methylhydrazono)methyl)-N-hydroxybenzamide (3f) on the acetylation of α-tubulin revealed an increased level of acetylation. These two compounds also affected cell migration, indicating their inhibition of HDAC6. An analysis of the antiproliferative activity of these compounds, which presented the most potent activity, showed that compound 3c induced cell cycle arrest and 3g induced apoptosis through caspase 3/7 activation. These results suggest HDAC6/8 as a potential target of future molecular therapies for cancer.

Evaluation of the catalytic properties of Burkholderia cepacia lipase immobilized on non-commercial matrices to be used in biodiesel synthesis from different feedstocks.

The objective of this work was to produce an immobilized form of lipase from Burkholderia cepacia (lipase PS) with advantageous catalytic properties and stability to be used in the ethanolysis of different feedstocks, mainly babassu oil and tallow beef. For this purpose lipase PS was immobilized on two different non-commercial matrices, such as inorganic matrix (niobium oxide, Nb(2)O(5)) and a hybrid matrix (polysiloxane-polyvinyl alcohol, SiO(2)-PVA) by covalent binding. The properties of free and immobilized enzymes were searched and compared. The best performance regarding all the analyzed parameters (biochemical properties, kinetic constants and thermal stability) were obtained when the lipase was immobilized on SiO(2)-PVA. The superiority of this immobilized system was also confirmed in the transesterification of both feedstocks, attained higher yields and productivities.