Toxic and non-toxic cyanobacterial biomass as a resource for sustainable agriculture: A lettuce cultivation experiment.

Cyanobacteria represent a promising resource for sustainable agriculture, as they have demonstrated the ability to restore soil fertility even after death and decay. However, several cyanobacteria can also release secondary metabolites, such as cyanotoxins, which may compromise the quality of agricultural products and pose a potential risk to human health. Depending on the concentration of exposure, few studies reported deleterious effects on plant species when irrigated with cylindrospermopsin (CYN) contaminated water, impairing plant growth and leading to food product contamination, while other studies show promoting effects on plant yield. To evaluate the potential of cyanobacterial biomass (cyanotoxin-containing or not) as a sustainable resource for soil amendment, biostimulants or fertilizers for lettuce cultivation, a study was carried out that consisted of the culture of lettuce plants under controlled conditions, in soil: (1) with no extra nutrient addition (control) and supplemented with 0.6 g of freeze-dried Raphidiopsis raciborskii biomass of (2) a non-CYN-producing strain, (3) a CYN-producing strain, and (4) the same CYN-producing strain pasteurized. Results showed no significant differences in photosystem II efficiency with the amendment addition. On the contrary, shoot fresh weight significantly increased in lettuce plants grown with the cyanobacterial biomass addition, especially in condition (3). In addition, there were significant differences in mineral concentrations in lettuce leaves after the cyanobacterial biomass addition, such as K, Na, Ca, P, Mg, Mn, Zn, Cu, Mo, and Co. CYN accumulation was detected under conditions (3) and (4), with concentrations observed in descending order from roots > soil > shoot. Nevertheless, the CYN concentration in edible tissues did not exceed the WHO-proposed tolerable daily intake of 0.03 µg/kg/day. These findings suggest that incorporating cyanobacterial biomass as a soil amendment, biostimulant or fertilizer for lettuce cultivation, even with trace amounts of CYN (1-40 µg/g), may enhance plant yield without leading to cyanotoxin accumulation in edible tissues above the WHO-recommended tolerable daily intake.

Unravelling the Influence of Endocrine-Disrupting Chemicals on Obesity Pathophysiology Pathways.

Obesity represents a global health concern, affecting individuals of all age groups across the world. The prevalence of excess weight and obesity has escalated to pandemic proportions, leading to a substantial increase in the incidence of various comorbidities, such as cardiovascular diseases, type 2 diabetes, and cancer. This chapter seeks to provide a comprehensive exploration of the pathways through which endocrine-disrupting chemicals can influence the pathophysiology of obesity. These mechanisms encompass aspects such as the regulation of food intake and appetite, intestinal fat absorption, lipid metabolism, and the modulation of inflammation. This knowledge may help to elucidate the role of exogenous molecules in both the aetiology and progression of obesity.

Phosphate-containing glycolipids: a review on synthesis and bioactivity.

Phosphate-containing glycolipids (PcGL) are scarcer than the better understood glycolipids. They are composed of arrangements of phosphate, carbohydrates and glycerol units and are always found associated with lipids. PcGL are often found associated with cell membranes, meaning their roles concern cell interactions. This article aims to provide an up-to-date overview of the existing knowledge and research on PcGL, emphasizing their synthesis and wide range of biological activities. When it comes to the synthesis of PcGL compounds, the strategies for glycosylation mainly rely on the thioglycoside donor, the trichloroacetmaidate donor and halide donor strategies, while phosphorylation is stapled and falls on either phosphite chemistry or phosphoryl chloride chemistry. Certain bacteria utilize PcGLs in their pathogenicity, triggering an inflammatory response within the host's defense mechanisms. The best-known examples of these structures are teichoic acids, lipopolysaccharide and the capsular polysaccharide found in bacteria, all of which are frequently implicated in bacterial infections. Given the degree of variability within PcGL structures, they were found to display a wide range of bioactivities. PcGL compounds were found to: (1) have anti-metastatic properties, (2) behave as agonists or antagonists of platelet aggregation, (3) be mostly pro-inflammatory, (4) display antifungal and antibiotic activity and (5) have neurogenic activity.

Liposomal quercetin: A promising strategy to combat hepatic insulin resistance and inflammation in type 2 diabetes mellitus.

In type 2 diabetes mellitus, hepatic insulin resistance is intricately associated with oxidative stress and inflammation. Nonetheless, the lack of therapeutic interventions directly targeting hepatic dysfunction represents a notable gap in current treatment options. Flavonoids have been explored due to their potential antidiabetic effects. However, these compounds are associated with low bioavailability and high metabolization. In the present study, four flavonoids, kaempferol, quercetin, kaempferol-7-O-glucoside and quercetin-7-O-glucoside, were studied in a cellular model of hepatic insulin resistance using HepG2 cells. Quercetin was selected as the most promising flavonoid and incorporated into liposomes to enhance its therapeutic effect. Quercetin liposomes had a mean size of 0.12 µm, with an incorporation efficiency of 93 %. Quercetin liposomes exhibited increased efficacy in modulating insulin resistance. This was achieved through the modulation of Akt expression and the attenuation of inflammation, particularly via the NF-κB pathway, as well as the regulation of PGE2 and COX-2 expression. Furthermore, quercetin liposomes displayed a significant advantage over free quercetin in attenuating the production of reactive pro-oxidant species. These findings open new avenues for developing innovative therapeutic strategies to manage diabetes, emphasizing the potential of quercetin liposomes as a promising approach for targeting both hepatic insulin resistance and associated inflammation.

Plant-derived and dietary phenolic cinnamic acid derivatives: Anti-inflammatory properties.

Cinnamic acids are aromatic acids primarily found in plants and plant-derived food. Phenolic cinnamic acids, with one or more hydroxyl groups in the aromatic ring, often contribute to the biological activities attributed to these compounds. The presence of hydroxyl groups and a carboxyl group makes cinnamic acids very hydrophilic, preventing them from crossing biological membranes and exerting their biological activities. To alleviate this condition, a panel of synthetic modifications have been made leading to a diverse set of phenolic cinnamic structures. In this review, an overview of the natural phenolic cinnamic acid derivatives and their plant sources (more than 200) is described. The synthetic approaches to obtain the referred derivatives (more than 200) namely esters and amides are reviewed. Further, their anti-inflammatory activity (more than 70 compounds) is scrutinized. Finally, future directions will be indicated to translate the research on phenolic cinnamic derivatives into potentially effective anti-inflammatory drugs.

Pyrazoles have a multifaceted anti-inflammatory effect targeting prostaglandin E2, cyclooxygenases and leukocytes' oxidative burst.

Elevated levels of prostaglandin E2 have been implicated in the pathophysiology of various diseases. Anti-inflammatory drugs that act through the inhibition of cyclooxygenase enzymatic activity, thereby leading to the suppression of prostaglandin E2, are often associated with several side effects due to their non-specific inhibition of cyclooxygenase enzymes. Consequently, the targeted suppression of prostaglandin E2 production with innovative molecules and/or mechanisms emerges as a compelling therapeutic strategy for the treatment of inflammatory-related diseases. Therefore, in this study, a systematic analysis of 28 pyrazole derivatives was conducted to explore their potential mechanisms for reducing prostaglandin E2 levels. In this context, the evaluation of these derivatives extended to examining their capacity to reduce prostaglandin E2in vitro in human whole blood, inhibit cyclooxygenase-1 and cyclooxygenase-2 enzymes, modulate cyclooxygenase-2 expression, and suppress oxidative burst in human leukocytes. The results enabled the establishment of significant structure-activity relationships, elucidating key determinants for their activities. In particular, the 4-styryl group on the pyrazole moiety and the presence of chloro substitutions were identified as key determinants. Pyrazole 8 demonstrated the capacity to reduce prostaglandin E2 levels by downregulating cyclooxygenase-2 expression, and pyrazole-1,2,3-triazole 18 emerged as a dual-acting agent, inhibiting human leukocytes' oxidative burst and cyclooxygenase-2 activity. Furthermore, pyrazole 26 demonstrated effective reduction of prostaglandin E2 levels through selective cyclooxygenase-1 inhibition. These results underscore the multifaceted anti-inflammatory potential of pyrazoles, providing new insights into the substitutions and structural frameworks that are beneficial for the studied activity.

Melanoxetin: A Hydroxylated Flavonoid Attenuates Oxidative Stress and Modulates Insulin Resistance and Glycation Pathways in an Animal Model of Type 2 Diabetes Mellitus.

Type 2 diabetes mellitus (DM) continues to escalate, necessitating innovative therapeutic approaches that target distinct pathways and address DM complications. Flavonoids have been shown to possess several pharmacological activities that are important for DM. This study aimed to evaluate the in vivo effects of the flavonoid melanoxetin using Goto-Kakizaki rats. Over a period of 14 days, melanoxetin was administered subcutaneously to investigate its antioxidant, anti-inflammatory, and antidiabetic properties. The results show that melanoxetin reduced insulin resistance in adipose tissue by targeting protein tyrosine phosphatase 1B. Additionally, melanoxetin counteracted oxidative stress by reducing nitrotyrosine levels and modulating superoxide dismutase 1 and hemeoxygenase in adipose tissue and decreasing methylglyoxal-derived hydroimidazolone (MG-H1), a key advanced glycation end product (AGE) implicated in DM-related complications. Moreover, the glyoxalase 1 expression decreased in both the liver and the heart, correlating with reduced AGE levels, particularly MG-H1 in the heart. Melanoxetin also demonstrated anti-inflammatory effects by reducing serum prostaglandin E2 levels, and increasing the antioxidant status of the aorta wall through enhanced acetylcholine-dependent relaxation in the presence of ascorbic acid. These findings provide valuable insights into melanoxetin's therapeutic potential in targeting multiple pathways involved in type 2 DM, particularly in mitigating oxidative stress and glycation.

Rheumatoid arthritis molecular targets and their importance to flavonoid-based therapy.

Rheumatoid arthritis (RA) is a progressive, chronic, autoimmune, inflammatory, and systemic condition that primarily affects the synovial joints and adjacent tissues, including bone, muscle, and tendons. The World Health Organization recognizes RA as one of the most prevalent chronic inflammatory diseases. In the last decade, there was an expansion on the available RA therapeutic options which aimed to improve patient's quality of life. Despite the extensive research and the emergence of new therapeutic approaches and drugs, there are still significant unwanted side effects associated to these drugs and still a vast number of patients that do not respond positively to the existing therapeutic strategies. Over the years, several references to the use of flavonoids in the quest for new treatments for RA have emerged. This review aimed to summarize the existing literature about the flavonoids' effects on the major pathogenic/molecular targets of RA and their potential use as lead compounds for the development of new effective molecules for RA treatment. It is demonstrated that flavonoids can modulate various players in synovial inflammation, regulate immune cell function, decrease synoviocytes proliferation and balance the apoptotic process, decrease angiogenesis, and stop/prevent bone and cartilage degradation, which are all dominant features of RA. Although further investigation is necessary to determine the effectiveness of flavonoids in humans, the available data from in vitro and in vivo models suggest their potential as new disease-modifying anti-rheumatic drugs. This review highlights the use of flavonoids as a promising avenue for future research in the treatment of RA.

Biodistribution and intestinal inflammatory response following voluntary oral intake of silver nanoparticles by C57BL/6J mice.

Silver nanoparticles (AgNP) are among the most widely commercialized nanomaterials globally, with applications in medicine and the food industry. Consequently, the increased use of AgNP in the food industry has led to an unavoidable rise  in human exposure to these nanoparticles. Their widespread use raises concerns about potential hazards to human health, specifically their intestinal pro-inflammatory effects. Thus, the main objective of this study was to evaluate the biological effects of two subacute doses of 5 nm polyvinylpyrrolidone (PVP)-AgNP in C57BL/6J mice. One mg/kg body weight or 10 mg/kg bw was provided once a day for 14 days, using a new technology (HaPILLness) that allows voluntary, stress-free, and accurate oral dosing. It was observed that after oral ingestion, while AgNP is biodistributed throughout the entire organism, most of the ingested dose is excreted in the feces. The passage and accumulation of AgNP throughout the intestine instigated a prominent inflammatory response, marked by significant histological, vascular, and cellular transformations. This response was driven by the activation of the nuclear factor-кB (NF-кB) inflammatory pathway, ultimately leading to the generation of multiple cytokines and chemokines.

Methodologies for Assessing Pancreatic Lipase Catalytic Activity: A Review.

Obesity is a disease of epidemic proportions with a concerning increasing trend. Regarded as one of the main sources of energy, lipids can also represent a big part of an unnecessary intake of calories and be, therefore, directly related to the problem of obesity. Pancreatic lipase is an enzyme that is essential in the absorption and digestion of dietary fats and has been explored as an alternative for the reduction of fat absorption and consequent weigh loss.Literature describes a great variability of methodologies and experimental conditions used in research to evaluate the in vitro inhibitory activity of compounds against pancreatic lipase. However, in an attempt to choose the best approach, it is necessary to know all the reaction conditions and understand how these can affect the enzymatic assay.The objective of this review is to understand and summarize the methodologies and respective experimental conditions that are mainly used to evaluate pancreatic lipase catalytic activity.156 studies were included in this work and a detailed description of the most commonly used UV/Vis spectrophotometric and fluorimetric instrumental techniques are presented, including a discussion regarding the differences found in the parameters used in both techniques, namely enzyme, substrate, buffer solutions, kinetics conditions, temperature and pH.This works shows that both UV/Vis spectrophotometry and fluorimetry are useful instrumental techniques for the evaluation of pancreatic lipase catalytic activity, presenting several advantages and limitations, which make the choice of parameters and experimental conditions a crucial decision to obtain the most reliable results.

The role of flavonoids in the regulation of epithelial-mesenchymal transition in cancer: A review on targeting signaling pathways and metastasis.

One of the hallmarks of cancer is metastasis, a process that entails the spread of cancer cells to distant regions in the body, culminating in tumor formation in secondary organs. Importantly, the proinflammatory environment surrounding cancer cells further contributes to cancer cell transformation and extracellular matrix destruction. During metastasis, front-rear polarity and emergence of migratory and invasive features are manifestations of epithelial-mesenchymal transition (EMT). A variety of transcription factors (TFs) are implicated in the execution of EMT, the most prominent belonging to the Snail Family Transcriptional Repressor (SNAI) and Zinc Finger E-Box Binding Homeobox (ZEB) families of TFs. These TFs are regulated by interaction with specific microRNAs (miRNAs), as miR34 and miR200. Among the several secondary metabolites produced in plants, flavonoids constitute a major group of bioactive molecules, with several described effects including antioxidant, antiinflammatory, antidiabetic, antiobesogenic, and anticancer effects. This review scrutinizes the modulatory role of flavonoids on the activity of SNAI/ZEB TFs and on their regulatory miRNAs, miR-34, and miR-200. The modulatory role of flavonoids can attenuate mesenchymal features and stimulate epithelial features, thereby inhibiting and reversing EMT. Moreover, this modulation is concomitant with the attenuation of signaling pathways involved in diverse processes as cell proliferation, cell growth, cell cycle progression, apoptosis inhibition, morphogenesis, cell fate, cell migration, cell polarity, and wound healing. The antimetastatic potential of these versatile compounds is emerging and represents an opportunity for the synthesis of more specific and potent agents.

Silver nanoparticles exert toxic effects in human monocytes and macrophages associated with the disruption of Δψm and release of pro-inflammatory cytokines.

Silver nanoparticles (AgNP) are the most widely produced type of nanoparticles due to their antimicrobial and preservative properties. However, their systemic bioavailability may be considered a potential hazard. When AgNP reach the bloodstream, they interact with the immune cells, contributing to the onset and development of an inflammatory response. Monocytes and macrophages play a pivotal role in our defense system, but the interaction of AgNP with these cells is still not clear. Therefore, the main objective of this work was to assess the cytotoxic and pro-inflammatory effects induced by 5, 10, and 50 nm AgNP coated with polyvinylpyrrolidone (PVP) and citrate, in concentrations that could be attained in vivo (0-25 µg/mL), in human monocytes isolated from human blood and human macrophages derived from a monocytic cell line (THP-1). The effects of PVP and citrate-coated AgNP on cell viability, mitochondrial membrane potential, and cytokines release were evaluated. The results evidenced that AgNP exert strong harmful effects in both monocytes and macrophages, through the establishment of a strong pro-inflammatory response that culminates in cell death. The observed effects were dependent on the AgNP concentration, size and coating, being observed more pronounced cytotoxic effects with smaller PVP coated AgNP. The results showed that human monocytes seem to be more sensitive to AgNP exposure than human macrophages. Considering the increased daily use of AgNP, it is imperative to further explore the adverse outcomes and mechanistic pathways leading to AgNP-induced pro-inflammatory effects to deep insight into the molecular mechanism involved in this effect.

Estratégias de ensino voltadas à assistência de enfermagem no acidente vascular cerebral: revisão integrativa* / Estrategias de enseñanza de la asistencia de enfermería en el ictus: una revisión integradora / Teaching strategies for nursing care in stroke: an integrative review

Objetivo: identificar as estratégias pedagógicas utilizadas no ensino da assistência de enfermagem às vítimas de acidente vascular cerebral. Método: revisão integrativa, realizada entre setembro de 2022 e março de 2023 em sete fontes de informações. Utilizou-se o aplicativo Rayyan para a seleção e a análise temática dos 485 manuscritos, destes, sete compuseram a amostra. Resultados: evidenciou-se como estratégias pedagógicas a simulação clínica, instrução interativa assistida por computador, videotape conduzido por instrutor, vinhetas, ferramenta multimídia de e-learning e o workshop. Conclusão: identificaram-se seis estratégias, com destaque para a simulação clínica por ter sido o método mais abordado pelos estudos como a única capaz de desenvolver, em conjunto, as habilidades cognitivas, psicomotoras e afetivas nos estudantes de enfermagem.

Objective: to identify the pedagogical strategies used in teaching nursing care to stroke victims. Method: integrative review, carried out between September 2022 and March 2023 in seven sources of information. The Rayyan application was used for the selection and thematic analysis of the 485 manuscripts, of which seven constituted the sample. Results: Clinical simulation, interactive computer-assisted instruction, instructor-led videotape, vignettes, multimedia e-learning tool and workshop were identified as pedagogical strategies. Conclusion: Six strategies were identified, with clinical simulation standing out as the method most often mentioned in studies as the only one capable of developing cognitive, psychomotor, and affective skills in nursing students.

Objetivo: identificar las estrategias pedagógicas utilizadas en la enseñanza de los cuidados de enfermería a las víctimas de accidentes cerebrovasculares. Método: revisión integradora, realizada entre septiembre de 2022 y marzo de 2023 sobre siete fuentes de información. Se utilizó la aplicación Rayyan para seleccionar y analizar temáticamente los 485 manuscritos, de los cuales siete constituyeron la muestra. Resultados: la simulación clínica, la enseñanza interactiva asistida por ordenador, los vídeos dirigidos por un instructor, las viñetas, las herramientas multimedia de aprendizaje electrónico y los talleres fueron las principales estrategias de enseñanza. Conclusión: Se identificaron seis estrategias, destacando la simulación clínica como el método más mencionado en los estudios como el único capaz de desarrollar habilidades cognitivas, psicomotoras y afectivas en los estudiantes de enfermería.

Updated Information of the Effects of (Poly)phenols against Type-2 Diabetes Mellitus in Humans: Reinforcing the Recommendations for Future Research.

(Poly)phenols have anti-diabetic properties that are mediated through the regulation of the main biomarkers associated with type 2 diabetes mellitus (T2DM) (fasting plasma glucose (FPG), glycated hemoglobin (HbA1c), insulin resistance (IR)), as well as the modulation of other metabolic, inflammatory and oxidative stress pathways. A wide range of human and pre-clinical studies supports these effects for different plant products containing mixed (poly)phenols (e.g., berries, cocoa, tea) and for some single compounds (e.g., resveratrol). We went through some of the latest human intervention trials and pre-clinical studies looking at (poly)phenols against T2DM to update the current evidence and to examine the progress in this field to achieve consistent proof of the anti-diabetic benefits of these compounds. Overall, the reported effects remain small and highly variable, and the accumulated data are still limited and contradictory, as shown by recent meta-analyses. We found newly published studies with better experimental strategies, but there were also examples of studies that still need to be improved. Herein, we highlight some of the main aspects that still need to be considered in future studies and reinforce the messages that need to be taken on board to achieve consistent evidence of the anti-diabetic effects of (poly)phenols.

Inhibition of the carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase by hydroxylated xanthones.

Xanthones are oxygen-containing heterocyclic compounds that exhibit a wide range of biological and pharmacological properties. Some natural and synthetic derivatives have been identified for their antidiabetic profile, mainly as α-glucosidase inhibitors. However, studies concerning the inhibition of both carbohydrate-hydrolyzing enzymes α-amylase and α-glucosidase are scarce. Thus, in order to identify some of these dual-target antidiabetic agents, a series of new synthetic xanthones were evaluated together with their commercial parents mangiferin (4), α-mangostin (5) and γ-mangostin (6). The results showed that xanthones exhibited a systematic stronger inhibition against α-glucosidase rather than for α-amylase. Derivatives 2c, 3a and 3b, bearing one catechol moiety, were the most active inhibitors of α-amylase, while xanthones 2c, 3b and 3c were the most active against α-glucosidase activity, with IC50 values lower than 10 µM. These findings suggest that the substitution pattern of the xanthone scaffold modulated the inhibitory activity of these compounds, and some structure-activity relationships could be established for both assays. In addition, the type of inhibition was also studied, and the results indicate a competitive type of inhibition for α-amylase activity by xanthones 2c, 3b, 3c and γ-mangostin (6). On the other hand, non-competitive inhibition mechanisms can be ascribed for all xanthones 1-6 against α-glucosidase. The present work can open a promising area of research based on the design of novel xanthone derivatives, based on natural ones, for targeting key enzymes involved in glucose metabolism and therefore in the management of type 2 diabetes mellitus.

A combined experimental and computational study to discover novel tyrosinase inhibitors.

Depigmenting properties of tyrosinase inhibitors (TAi) boosted the search for new compounds applicable in cosmetics. Kojic acid, a 3-hydroxy-4-pyrone, is the most studied tyrosinase inhibitor but undesirable side effects, like dermatitis, and unspecified mechanism led to its exclusion in several countries. To discover safer and more efficient TA, we evaluated tyrosinase inhibitory effect of twelve 3-hydroxy-4-pyridinones (3,4-HPO) in vitro and considering the two reaction steps of inhibition in mushroom tyrosinase enzyme. In parallel we performed molecular docking studies in human and mushroom enzymes. Ligands I6 and I11 were the most effective compounds considering their inhibitory activity in both reaction steps. Our studies revealed that I6 has a non-competitive and mixed type of inhibition for monophenolase and diphenolase activity, while ligand I11 showed a mixed and competitive inhibition type for each reaction step. Molecular Docking results indicated that ligands tend to bind the enzyme by coordinating directly with the binuclear cooper centre and highlighted the relevance of voluminous and non-polar substituents at R2 to avoid the binding of the ligands to the enzyme. The work clarifies the type of inhibition established for kojic acid and points out the differences found for the set of 3,4-HPO chelators studied as prospective tyrosinase inhibitors.

2-Styrylchromones: Cytotoxicity and Modulation of Human Neutrophils' Oxidative Burst.

Neutrophils are polymorphonuclear leukocytes recruited to sites of acute inflammation, in response to pathogen invasion and tissue injury. The modulation of their activity, especially oxidative burst, may be important to control the inflammatory process. 2-Styrylchromones (2-SC) are derived from chromones and despite their recognized multiple biological activities, their anti-inflammatory and antioxidant properties are still poorly explored. Therefore, in this study, 43 structurally related 2-SC were evaluated concerning their effects on freshly isolated human neutrophils' viability and oxidative burst. The studied 2-SC were divided into eight groups according to their substitution at C-4' on B-ring (none, -OH, -OCH3, -OBn, -CH3, and -NO2), existence and location of -Cl on B-ring, and presence of -Br at C-3 on C-ring. Overall, most of the studied 2-SC did not affect neutrophils' viability, at physiological relevant concentrations. The ones belonging to B group were the most effective (IC50 values < 2 µM), and present one -OH group at C-4' or a catechol group at C-3' and C-4' on B-ring. These substituents seem to play an important role in the modulatory activity of human neutrophils' oxidative burst. These results reinforce the great potential of 2-SC's scaffold for the development of new anti-inflammatory agents.

Pro-inflammatory effects of silver nanoparticles in the intestine.

Nanotechnology is a promising technology of the twenty-first century, being a rapidly evolving field of research and industrial innovation widely applied in our everyday life. Silver nanoparticles (AgNP) are considered the most commercialized nanosystems worldwide, being applied in diverse sectors, from medicine to the food industry. Considering their unique physical, chemical and biological properties, AgNP have gained access into our daily life, with an exponential use in food industry, leading to an increased inevitable human oral exposure. With the growing use of AgNP, several concerns have been raised, in recent years, about their potential hazards to human health, more precisely their pro-inflammatory effects within the gastrointestinal system. Therefore a review of the literature has been undertaken to understand the pro-inflammatory potential of AgNP, after human oral exposure, in the intestine. Despite the paucity of information reported in the literature about this issue, existing studies indicate that AgNP exert a pro-inflammatory action, through generation of oxidative stress, accompanied by mitochondrial dysfunction, interference with transcription factors and production of cytokines. However, further studies are needed to elucidate the mechanistic pathways and molecular targets involved in the intestinal pro-inflammatory effects of AgNP.

An In Silico and an In Vitro Inhibition Analysis of Glycogen Phosphorylase by Flavonoids, Styrylchromones, and Pyrazoles.

Glycogen phosphorylase (GP) is a key enzyme in the glycogenolysis pathway. GP inhibitors are currently under investigation as a new liver-targeted approach to managing type 2 diabetes mellitus (DM). The aim of the present study was to evaluate the inhibitory activity of a panel of 52 structurally related chromone derivatives; namely, flavonoids, 2-styrylchromones, 2-styrylchromone-related derivatives [2-(4-arylbuta-1,3-dien-1-yl)chromones], and 4- and 5-styrylpyrazoles against GP, using in silico and in vitro microanalysis screening systems. Several of the tested compounds showed a potent inhibitory effect. The structure-activity relationship study indicated that for 2-styrylchromones and 2-styrylchromone-related derivatives, the hydroxylations at the A and B rings, and in the flavonoid family, as well as the hydroxylation of the A ring, were determinants for the inhibitory activity. To support the in vitro experimental findings, molecular docking studies were performed, revealing clear hydrogen bonding patterns that favored the inhibitory effects of flavonoids, 2-styrylchromones, and 2-styrylchromone-related derivatives. Interestingly, the potency of the most active compounds increased almost four-fold when the concentration of glucose increased, presenting an IC50 < 10 µM. This effect may reduce the risk of hypoglycemia, a commonly reported side effect of antidiabetic agents. This work contributes with important considerations and provides a better understanding of potential scaffolds for the study of novel GP inhibitors.

Inhibitory activity of flavonoids against human sucrase-isomaltase (α-glucosidase) activity in a Caco-2/TC7 cellular model.

Type 2 diabetes (T2D) is the most common form of diabetes, and the number of people with this metabolic disease is steadily increasing worldwide. Among the available antidiabetic agents, α-glucosidase inhibitors are the most effective at reducing postprandial hyperglycaemia (PPHG), one of the main characteristics of T2D. However, most of the studies that have been performed have used the more readily available rat intestinal preparations or yeast α-glucosidase as the enzyme source, which despite being useful and cost effective, have a questionable physiological value. The present study evaluates the inhibitory activity of a selected group of flavonoids against human sucrase-isomaltase (SI), the α-glucosidase found in Caco-2/TC7 cells. A microassay using the physiological substrates sucrose and maltose, and a synthetic substrate, p-nitrophenyl-α-D-glucopyranoside (pNPG) was performed. The most active flavonoid was compound 4 (melanoxetin), presenting an IC50 value similar using the two natural substrates. In contrast, the tested flavonoids were not effective at inhibiting SI, when pNPG was used as a substrate. Hydroxylation of flavonoids at C-3 of the C ring, at C-3' and C-4' of the B ring, and at C-7 and C-8 of the A ring were the features that improved the inhibitory activity of flavonoids against human SI. These phenolic compounds deserve further exploration as alternatives to the currently available α-glucosidase inhibitors. The present study also demonstrates that the non-clinical in vitro studies conducted for the evaluation of α-glucosidase activity should use the human source rather than surrogate sources of α-glucosidase.