Repurposing antiplasmodial leads for cancer: Exploring the antiproliferative effects of N-cinnamoyl-aminoacridines.

Drug repurposing and rescuing have been widely explored as cost-effective approaches to expand the portfolio of chemotherapeutic agents. Based on the reported antitumor properties of both trans-cinnamic acids and quinacrine, an antimalarial aminoacridine, we explored the antiproliferative properties of two series of N-cinnamoyl-aminoacridines recently identified as multi-stage antiplasmodial leads. The compounds were evaluated in vitro against three cancer cell lines (MKN-28, Huh-7, and HepG2), and human primary dermal fibroblasts. One of the series displayed highly selective antiproliferative activity in the micromolar range against the three cancer cell lines tested, without any toxicity to non-carcinogenic cells.

Betulinic Acid for Glioblastoma Treatment: Reality, Challenges and Perspectives.

Betulinic acid is a naturally occurring compound that can be obtained through methanolic or ethanolic extraction from plant sources, as well as through chemical synthesis or microbial biotransformation. Betulinic acid has been investigated for its potential therapeutic properties, and exhibits anti-inflammatory, antiviral, antimalarial, and antioxidant activities. Notably, its ability to cross the blood-brain barrier addresses a significant challenge in treating neurological pathologies. This review aims to compile information about the impact of betulinic acid as an antitumor agent, particularly in the context of glioblastoma. Importantly, betulinic acid demonstrates selective antitumor activity against glioblastoma cells by inhibiting proliferation and inducing apoptosis, consistent with observations in other cancer types. Compelling evidence published highlights the acid's therapeutic action in suppressing the Akt/NFκB-p65 signaling cascade and enhancing the cytotoxic effects of the chemotherapeutic agent temozolomide. Interesting findings with betulinic acid also suggest a focus on researching the reduction of glioblastoma's invasiveness and aggressiveness profile. This involves modulation of extracellular matrix components, remodeling of the cytoskeleton, and secretion of proteolytic proteins. Drawing from a comprehensive review, we conclude that betulinic acid formulations as nanoparticles and/or ionic liquids are promising drug delivery approaches with the potential for translation into clinical applications for the treatment and management of glioblastoma.

AGPs as molecular determinants of reproductive development.

BACKGROUND AND AIMS: Morphogenesis occurs through accurate interaction between essential players to generate highly specialized plant organs. Fruit structure and function are triggered by a neat transcriptional control involving distinct regulator genes encoding transcription factors (TFs) or signalling proteins, such as the C2H2/C2HC zinc-finger NO TRANSMITTING TRACT (NTT) or the MADS-box protein SEEDSTICK (STK), which are important in setting plant reproductive competence, feasibly by affecting cell wall polysaccharide and lipid distribution. Arabinogalactan proteins (AGPs) are major components of the cell wall and are thought to be involved in the reproductive process as important players in specific stages of development. The detection of AGPs epitopes in reproductive tissues of NTT and other fruit development-related TFs, such as MADS-box proteins including SHATTERPROOF1 (SHP1), SHP2 and STK, was the focus of this study. METHODS: We used fluorescence microscopy to perform immunolocalization analyses on stk and ntt single mutants, on the ntt stk double mutant and on the stk shp1 shp2 triple mutant using specific anti-AGP monoclonal antibodies. In these mutants, the expression levels of selected AGP genes were also measured by quantitative real-time PCR and compared with the respective expression in wild-type (WT) plants. KEY RESULTS: The present immunolocalization study collects information on the distribution patterns of specific AGPs in Arabidopsis female reproductive tissues, complemented by the quantification of AGP expression levels, comparing WT, stk and ntt single mutants, the ntt stk double mutant and the stk shp1 shp2 triple mutant. CONCLUSIONS: These findings reveal distinct AGP distribution patterns in different developmental mutants related to the female reproductive unit in Arabidopsis. The value of the immunofluorescence labelling technique is highlighted in this study as an invaluable tool to dissect the remodelling nature of the cell wall in developmental processes.

Improving the Antimycobacterial Drug Clofazimine through Formation of Organic Salts by Combination with Fluoroquinolones.

This work reports the synthesis, structural and thermal analysis, and in vitro evaluation of the antimicrobial activity of two new organic salts (OSs) derived from the antimycobacterial drug clofazimine and the fluoroquinolones ofloxacin or norfloxacin. Organic salts derived from active pharmaceutical ingredients (API-OSs), as those herein disclosed, hold promise as cost-effective formulations with improved features over their parent drugs, thus enabling the mitigation of some of their shortcomings. For instance, in the specific case of clofazimine, its poor solubility severely limits its bioavailability. As compared to clofazimine, the clofazimine-derived OSs now reported have improved solubility and thermostability, without any major deleterious effects on the drug's bioactivity profile.

A Critical Comparison of the Advanced Extraction Techniques Applied to Obtain Health-Promoting Compounds from Seaweeds.

Marine macroalgae are rich in bioactive compounds that can be applied in several fields, mainly food, cosmetics, and medicine. The health-promoting effects of bioactive compounds, such as polyphenols, polysaccharides, carotenoids, proteins, and fatty acids, have been increasingly explored, especially regarding their antioxidant activity and improvement in human health. To extract these valuable compounds, advanced technologies that include Supercritical-Fluid Extraction (SFE), Pressurised-Liquid Extraction (PLE), Ultrasound-Assisted Extraction (UAE), Microwave-Assisted Extraction (MAE), Enzyme-Assisted Extraction (EAE), Ultrasound-Microwave-Assisted Extraction (UMAE) and Liquefied Gas Extraction (LGE) have been assessed due to their notable advantages over the conventional methods (Solid-Liquid and Soxhlet extraction). These advanced techniques are considerably influenced by different extraction parameters such as temperature, pressure, type of solvent, extraction time, solvent:solid material ratio, power (MAE, UAE, and UMAE), enzymes used (EAE), and factors related to the macroalgae matrix itself. Optimizing these process parameters for each method is critical to obtain better efficiency results for the targeted bioactive compounds. Macroalgae are natural sources with undeniable beneficial effects on human health. In this context, optimising the extraction techniques discussed in this review should prioritise exploiting these valuable resources' wide range of bioactive properties.

New Perspectives on the Sustainable Employment of Chestnut Shells as Active Ingredient against Oral Mucositis: A First Screening.

Oral mucositis (OM), a common side effect of oncological treatment, is an oral mucosal disorder characterized by painful ulcerations and increased risk of infection. The use of natural antioxidants to suppress the redox imbalance responsible for the OM condition has emerged as an interesting approach to prevent/treat OM. This study aims to explore the chestnut (Castana sativa) shells as potential active ingredient against OM. Therefore, chestnut shells were extracted at different temperatures (110-180 °C) by Subcritical Water Extraction (SWE), aiming to recover antioxidants. The extracts were also evaluated against microorganisms present in the oral cavity as well as on human oral cell lines (TR146 and HSC3). The highest phenolic content was obtained with the extraction temperature of 110 °C, exhibiting the best antioxidant/antiradical activities and scavenging efficiencies against HOCl (IC50 = 4.47 µg/mL) and ROO• (0.73 µmol TE/mg DW). High concentrations of phenolic acids (e.g., gallic and protocatechuic acids) and flavanoids (catechin, epicatechin and rutin) characterized the phenolic profile. The antimicrobial activity against several oral microorganisms present in the oral cavity during OM, such as Streptococcus, Staphylococcus, Enterococcus, and Escherichia, was demonstrated. Finally, the effects on HSC3 and TR146 cell lines revealed that the extract prepared at 110 °C had the lowest IC50 (1325.03 and 468.15 µg/mL, respectively). This study highlights the potential effects of chestnut shells on OM.

Effect of Blood Flow Restriction Technique on Delayed Onset Muscle Soreness: A Systematic Review.

Background and Objectives: The effect of the blood flow restriction technique (BFR) on delayed onset muscular soreness (DOMS) symptoms remains unclear. Since there is no consensus in the literature, the aim of the present study is to systematically identify and appraise the available evidence on the effects of the BFR technique on DOMS, in healthy subjects. Materials and Methods: Computerized literature search in the databases Pubmed, Google Scholar, EBSCO, Cochrane and PEDro to identify randomized controlled trials that assessed the effects of blood flow restriction on delayed onset muscular soreness symptoms. Results: Eight trials met the eligibility criteria and were included in this review, presenting the results of 118 participants, with a mean methodological rating of 6/10 on the PEDro scale. Conclusions: So far, there is not enough evidence to confirm or refute the influence of BFR on DOMS, and more studies with a good methodological basis are needed, in larger samples, to establish protocols and parameters of exercise and intervention. Data analysis suggests a tendency toward the proinflammatory effect of BFR during high restrictive pressures combined with eccentric exercises, while postconditioning BFR seems to have a protective effect on DOMS. Prospero ID record: 345457, title registration: "Effect of Blood Flow Restriction Technique on the Prevention of Delayed Onset Muscle Soreness: A Systematic Review".

Bridging Cyanobacteria to Neurodegenerative Diseases: A New Potential Source of Bioactive Compounds against Alzheimer's Disease.

Neurodegenerative diseases (NDs) represent a drawback in society given the ageing population. Dementias are the most prevalent NDs, with Alzheimer's disease (AD) representing around 70% of all cases. The current pharmaceuticals for AD are symptomatic and with no effects on the progression of the disease. Thus, research on molecules with therapeutic relevance has become a major focus for the scientific community. Cyanobacteria are a group of photosynthetic prokaryotes rich in biomolecules with confirmed activity in pathologies such as cancer, and with feasible potential in NDs such as AD. In this review, we aimed to compile the research works focused in the anti-AD potential of cyanobacteria, namely regarding the inhibition of the enzyme ß-secretase (BACE1) as a fundamental enzyme in the generation of ß-amyloid (Aß), the inhibition of the enzyme acetylcholinesterase (AChE) lead to an increase in the availability of the neurotransmitter acetylcholine in the synaptic cleft and the antioxidant and anti-inflammatory effects, as phenomena associated with neurodegeneration mechanisms.

The Emerging Role of Ionic Liquid-Based Approaches for Enhanced Skin Permeation of Bioactive Molecules: A Snapshot of the Past Couple of Years.

Topical and transdermal delivery systems are of undeniable significance and ubiquity in healthcare, to facilitate the delivery of active pharmaceutical ingredients, respectively, onto or across the skin to enter systemic circulation. From ancient ointments and potions to modern micro/nanotechnological devices, a variety of approaches has been explored over the ages to improve the skin permeation of diverse medicines and cosmetics. Amongst the latest investigational dermal permeation enhancers, ionic liquids have been gaining momentum, and recent years have been prolific in this regard. As such, this review offers an outline of current methods for enhancing percutaneous permeation, highlighting selected reports where ionic liquid-based approaches have been investigated for this purpose. Future perspectives on use of ionic liquids for topical delivery of bioactive peptides are also presented.

The Effect of Warm-up Running Technique on Sprint Performance.

ABSTRACT: Gil, MH, Neiva, HP, Alves, AR, Sousa, AC, Ferraz, R, Marques, MC, and Marinho, DA. The effect of warm-up running technique on sprint performance. J Strength Cond Res 35(12): 3341-3347, 2021-The purpose of the current study was to analyze the effect of changing the running technique during warm-up on sprint performances, running biomechanics, physiological, and psychophysiological responses. Thirty-one physically active men aged 18-23 years (mean ± SD: 19.35 ± 1.08 years of age; 1.77 ± 0.07 m of height; 71.90 ± 10.37 kg of body mass) volunteered to participate and randomly performed 2 maximal 30-m sprints, 5 minutes after completing a warm-up focused on increased stride length-SL (WUL) or a warm-up focused on increased stride frequency-SF (WUF). The results showed that there were no differences between the 30-m sprint performances and in running biomechanics. However, WUF showed increased performances in the first 15 m of the race (WUF: 2.59 ± 0.11 seconds vs. WUL: 2.63 ± 0.15 seconds; p = 0.03), and WUL resulted in higher performances in the last 15 m (1.94 ± 0.19 seconds vs. 1.88 ± 0.09 seconds; p = 0.05). In the second 30-m time trial, WUF also resulted in faster starting 15 m of the race (2.58 ± 0.12 seconds vs. 2.63 ± 0.16 seconds; p = 0.04). Interestingly, the WUF was the warm-up that revealed more stability in performances and running biomechanics between both trials. These results showed that there were no significant differences between warm-ups comprising exercises focusing in higher SL or higher SF in 30-m sprint biomechanics and performance. Nevertheless, different running strategies were caused by those 2 warm-ups and a more stabilized running pattern, and performance values were found when warm-up focused on higher SF.

Effects of Match Location, Quality of Opposition and Match Outcome on Match Running Performance in a Portuguese Professional Football Team.

The aim of this study was to analyze the effects of match location, quality of opposition and match outcome on match running performance according to playing position in a Portuguese professional football team. Twenty-three male professional football players were monitored from eighteen Portuguese Football League matches during the 2019-2020 season. Global positioning system technology (GPS) was used to collect time-motion data. The match running performance was obtained from five playing positions: central defenders (CD), fullbacks (FB), central midfielders (CM), wide midfielders (WM) and forwards (FW). Match running performance was analyzed within specific position and contextual factors using one-way analysis of variance (ANOVA) for repeated measures, standardized (Cohen) differences and smallest worthwhile change. CM and WM players covered significantly greater total distance (F = 15.45, p = 0.000, η2 = 0.334) and average speed (F = 12.79, p < 0.001, η2 = 0.294). WM and FB players covered higher distances at high-speed running (F = 16.93, p = 0.000, η2 = 0.355) and sprinting (F = 13.49; p < 0.001, η2 = 0.305). WM players covered the highest number of accelerations (F = 4.69, p < 0.001, η2 = 0.132) and decelerations (F = 12.21, p < 0.001, η2 = 0.284). The match running performance was influenced by match location (d = 0.06-2.04; CI: -0.42-2.31; SWC = 0.01-1.10), quality of opposition (d = 0.13-2.14; CI: -0.02-2.60; SWC = 0.01-1.55) and match outcome (d = 0.01-2.49; CI: -0.01-2.31; SWC = 0.01-0.35). Contextual factors influenced the match running performance with differential effects between playing positions. This study provides the first report about the contextual influence on match running performance in a Portuguese professional football team. Future research should also integrate tactical and technical key indicators when analyzing the match-related contextual influence on match running performance.

Building on Surface-Active Ionic Liquids for the Rescuing of the Antimalarial Drug Chloroquine.

Ionic liquids derived from classical antimalarials are emerging as a new approach towards the cost-effective rescuing of those drugs. Herein, we disclose novel surface-active ionic liquids derived from chloroquine and natural fatty acids whose antimalarial activity in vitro was found to be superior to that of the parent drug. The most potent ionic liquid was the laurate salt of chloroquine, which presented IC50 values of 4 and 110 nM against a chloroquine-sensitive and a chloroquine-resistant strain of Plasmodium falciparum, respectively, corresponding to an 11- and 6-fold increase in potency as compared to the reference chloroquine bisphosphate salt against the same strains. This unprecedented report opens new perspectives in both the fields of malaria chemotherapy and of surface-active ionic liquids derived from active pharmaceutical ingredients.

The Impact of [C16Pyr][Amp] on the Aggressiveness in Breast and Prostate Cancer Cell Lines.

Breast (BrCa) and prostate (PCa) cancers are the most common malignancies in women and men, respectively. The available therapeutic options for these tumors are still not curative and have severe side effects. Therefore, there is an urgent need for more effective antineoplastic agents. Herein, BrCa, PCa, and benign cell lines were treated with two ionic liquids and two quinoxalines and functional experiments were performed-namely cell viability, apoptosis, cytotoxicity, and colony formation assays. At the molecular level, an array of gene expressions encompassing several molecular pathways were used to explore the impact of treatment on gene expression. Although both quinoxalines and the ionic liquid [C2OHMIM][Amp] did not show any effect on the BrCa and PCa cell lines, [C16Pyr][Amp] significantly decreased cell viability and colony formation ability, while it increased the apoptosis levels of all cell lines. Importantly, [C16Pyr][Amp] was found to be more selective for cancer cells and less toxic than cisplatin. At the molecular level, this ionic liquid was also associated with reduced expression levels of CPT2, LDHA, MCM2, and SKP2, in both BrCa and PCa cell lines. Hence, [C16Pyr][Amp] was shown to be a promising anticancer therapeutic agent for BrCa and PCa cell lines.

"Clicking" an Ionic Liquid to a Potent Antimicrobial Peptide: On the Route towards Improved Stability.

A covalent conjugate between an antibacterial ionic liquid and an antimicrobial peptide was produced via "click" chemistry, and found to retain the parent peptide's activity against multidrug-resistant clinical isolates of Gram-negative bacteria, and antibiofilm action on a resistant clinical isolate of Klebsiella pneumoniae, while exhibiting much improved stability towards tyrosinase-mediated modifications. This unprecedented communication is a prelude for the promise held by ionic liquids -based approaches as tools to improve the action of bioactive peptides.

Differential effects of antiepileptic drugs on human bone cells.

Antiepileptic drugs (AED) have been associated to in vivo deleterious consequences in bone tissue. The present work aimed to characterize the cellular and molecular effects of five different AED on human osteoclastogenesis and osteblastogenesis. It was observed that the different drugs had the ability to differentially modulate both processes, in a way dependent on the identity and dose of the AED. Shortly, valproic acid stimulated either osteoclastogenesis and osteoblastogenesis, whereas carbamazepine, gabapentin, and lamotrigine revealed an opposite behavior; topiramate elicited a decrease of osteoclast development and an increase in osteoblast differentiation. This is the first report describing the direct effects of different AED on human primary bone cells, which is a very important issue, because these drugs are usually consumed in long-term therapeutics, with acknowledged in vivo effects in bone tissue.

Cinnamic Acid Conjugates in the Rescuing and Repurposing of Classical Antimalarial Drugs.

Cinnamic acids are compounds of natural origin that can be found in many different parts of a wide panoply of plants, where they play the most diverse biological roles, often in a conjugated form. For a long time, this has been driving Medicinal Chemists towards the investigation of the therapeutic potential of natural, semi-synthetic, or fully synthetic cinnamic acid conjugates. These efforts have been steadily disclosing promising drug leads, but a wide chemical space remains that deserves to be further explored. Amongst different reported approaches, the combination or conjugation of cinnamic acids with known drugs has been addressed in an attempt to produce either synergistic or multi-target action. In this connection, the present review will focus on efforts of the past decade regarding conjugation with cinnamic acids as a tool for the rescuing or the repurposing of classical antimalarial drugs, and also on future perspectives in this particular field of research.

Chloroquine Analogues as Leads against Pneumocystis Lung Pathogens.

The impact of Pneumocystis pneumonia (PcP) on morbidity and mortality remains substantial for immunocompromised individuals, including those afflicted by HIV infection, organ transplantation, cancer, autoimmune diseases, or subject to chemotherapy or corticosteroid-based therapies. Previous work from our group has shown that repurposing antimalarial compounds for PcP holds promise for treatment of this opportunistic infection. Following our previous discovery of chloroquine analogues with dual-stage antimalarial action both in vitro and in vivo, we now report the potent action of these compounds on Pneumocystis carinii in vitro Identification of chloroquine analogues as anti-PcP leads is an unprecedented finding.

Effects of knowing the task duration on players' pacing patterns during soccer small-sided games.

The aim of this study was to identify the influence of prior knowledge of exercise duration on players' pacing patterns during soccer small-sided games. Twenty semi-professional male soccer players participated in this study. In the first game scenario, players were not informed how long they would be required to play the small-sided game and the activity was terminated after 20 min (Unknown Condition). In the second game scenario, players were told that they would play the small-sided game for 10 min, but immediately after completing the 10-min game, they were asked to complete another 10 min (Partially Condition). In the third game scenario, players were instructed that they would play the small-sided game for 20 min and then they completed the 20-min game (Known Condition). The results presented a tendency of higher values in all performance variables in the [0'-10'] min compared with the [10'-20'] min. As the players' previous knowledge about the tasks duration increased, the performance between two moments tended to be similar. Considering the entire 20-min game duration, the Partially Condition of the exercise was the most demanding condition. In conclusion, the knowledge of shorter durations of the exercise seems to lead to an increase of exercise duration demand, and longer exercise durations possibly tend to decrease differences between full knowledge and not knowing the exercise duration.

Effects of novel triple-stage antimalarial ionic liquids on lipid membrane models.

Primaquine-based ionic liquids, obtained by acid-base reaction between parent primaquine and cinnamic acids, were recently found as triple-stage antimalarial hits. These ionic compounds displayed significant activity against both liver- and blood-stage Plasmodium parasites, as well as against stage V P. falciparum parasites. Remarkably, blood-stage activity of the ionic liquids against both chloroquine-sensitive (3D7) and resistant (Dd2) P. falciparum strains was clearly superior to those of the respective covalent (amide) analogues and of parent primaquine. Having hypothesized that such behaviour might be ascribed to an enhanced ability of the ionic compounds to permeate into Plasmodium-infected erythrocytes, we have carried out a differential scanning calorimetry-based study of the interactions between the ionic liquids and membrane models. Results provide evidence, at the molecular level, that the primaquine-derived ionic liquids may contribute to an increased permeation of the parent drug into malaria-infected erythrocytes, which has relevant implications towards novel antimalarial approaches based on ionic liquids.

Wound-Healing Peptides for Treatment of Chronic Diabetic Foot Ulcers and Other Infected Skin Injuries.

As the incidence of diabetes continues to increase in the western world, the prevalence of chronic wounds related to this condition continues to be a major focus of wound care research. Additionally, over 50% of chronic wounds exhibit signs and symptoms that are consistent with localized bacterial biofilms underlying severe infections that contribute to tissue destruction, delayed wound-healing and other serious complications. Most current biomedical approaches for advanced wound care aim at providing antimicrobial protection to the open wound together with a matrix scaffold (often collagen-based) to boost reestablishment of the skin tissue. Therefore, the present review is focused on the efforts that have been made over the past years to find peptides possessing wound-healing properties, towards the development of new and effective wound care treatments for diabetic foot ulcers and other skin and soft tissue infections.