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Podophyllotoxin is a natural compound belonging to the lignan family and is well-known for its great antitumor activity. However, it shows several limitations, such as severe side effects and some pharmacokinetics problems, including low water solubility, which hinders its application as an anticancer agent. Over the past few years, antitumor research has been focused on developing nanotechnology-based medicines or nanomedicines which allow researchers to improve the pharmacokinetic properties of anticancer compounds. Following this trend, podophyllotoxin nanoconjugates have been obtained to overcome its biopharmaceutical drawbacks and to enhance its antitumor properties. The objective of this review is to highlight the advances made over the past few years (2017–2023) regarding the inclusion of podophyllotoxin in different nanosystems. Among the huge variety of nanoconjugates of diverse nature, drug delivery systems bearing podophyllotoxin as cytotoxic payload are organic nanoparticles mainly based on polymer carriers, micelles, and liposomes. Along with the description of their pharmacological properties as antitumorals and the advantages compared to the free drug in terms of biocompatibility, solubility, and selectivity, we also provide insight into the synthetic procedures developed to obtain those podophyllotoxin-nanocarriers. Typical procedures in this regard are self-assembly techniques, nanoprecipitations, or ionic gelation methods among others. This comprehensive perspective aims to enlighten the medicinal chemistry community about the tendencies followed in the design of new podophyllotoxin-based drug delivery systems, their features and applications.

This study investigates the optimization of the Material Extrusion (MEX) process for producing polylactic acid (PLA) patterns used in investment casting moulds, specifically targeting the casting of non-ferrous alloys such as brass. Key MEX process parameters—layer thickness, wall thickness, infill density, and post-processing with dichloromethane vapour for surface enhancement—were systematically analyzed for their impact on mould quality. Results indicate that an optimized combination of MEX parameters yields moulds with high dimensional accuracy, low surface roughness, and minimal pattern residue within the mould cavity. These optimized moulds were subsequently used in brass casting, with the final cast parts evaluated for dimensional precision and surface finish. The study concludes that PLA patterns manufactured via optimized MEX parameters provide a precise, cost-effective, and easy-to-implement solution for industry applications. Additionally, this process is environmentally friendly and presents clear advantages over other pattern-making methods, offering a sustainable alternative for producing complex metal parts with reduced environmental impact. The findings underscore the significant role of post-processing in enhancing mould quality and, consequently, the quality of the cast parts.

Podophyllotoxin is a naturally occurring cyclolignan isolated from rhizomes of Podophyllum sp. In the clinic, it is used mainly as an antiviral; however, its antitumor activity is even more interesting. While podophyllotoxin possesses severe side effects that limit its development as an anticancer agent, nevertheless, it has become a good lead compound for the synthesis of derivatives with fewer side effects and better selectivity. Several examples, such as etoposide, highlight the potential of this natural product for chemomodulation in the search for new antitumor agents. This review focuses on the recent chemical modifications (2017–mid-2023) of the podophyllotoxin skeleton performed mainly at the C-ring (but also at the lactone D-ring and at the trimethoxyphenyl E-ring) together with their biological properties. Special emphasis is placed on hybrids or conjugates with other natural products (either primary or secondary metabolites) and other molecules (heterocycles, benzoheterocycles, synthetic drugs, and other moieties) that contribute to improved podophyllotoxin bioactivity. In fact, hybridization has been a good strategy to design podophyllotoxin derivatives with enhanced bioactivity. The way in which the two components are joined (directly or through spacers) was also considered for the organization of this review. This comprehensive perspective is presented with the aim of guiding the medicinal chemistry community in the design of new podophyllotoxin-based drugs with improved anticancer properties.

Studies on African medicinal plants have been limited to some geographically areas, and even though more than 5400 medicinal plants are recognized and documented, other valuable medicinal plant species have not been studied. Ethnopharmacological studies are important for documenting traditional knowledge associated with the medical use of biodiversity. This study aims to document the use of medicinal plants from the Province of Cuanza Norte (Angola). The field work was conducted from December 2018 to January 2019 and the ethnobotanical data were collected using semi-structured interviews. Informants were selected in accordance with their residence and community recognition as healers. Recorded plants are listed along with their popular name, traditional use, part used, and method of preparation. A total of 131 species of medicinal plants were cited. Mukumbi (Lannea welwitschii), Santa Maria (Chenopodium ambrosioides) and Ditumbata (Boerhavia difusa) were the most cited species. Out of the total plant parts, leaves were the most frequently material used. Regarding the mode of preparation for the medicinal materials, the major form of preparation is maceration, followed by infusion and decoction. The main categories of use were infectious and parasitic diseases (e.g., Malaria); undefined pains and illness; diseases of the digestive system; and endocrine, nutritional, and metabolic diseases (e.g., Diabetes). This study revealed the importance of preserving the ethnobotanical knowledge in order to protect the biodiversity and to discover new therapeutic molecules. A comparison of the results with other studies showed that some of the traditional indications are supported by data from scientific literature.

Exact numerical schemes have previously been obtained for some linear retarded delay differential equations and systems. Those schemes were derived from explicit expressions of the exact solutions, and were expressed in the form of perturbed difference systems, involving the values at previous delay intervals. In this work, we propose to directly obtain expressions of the same type for the fundamental solutions of linear delay differential equations, by considering vector equations with vector components corresponding to delay-lagged values at previous intervals. From these expressions for the fundamental solutions, exact numerical schemes for arbitrary initial functions can be proposed, and they may also facilitate obtaining explicit exact solutions. We apply this approach to obtain an exact numerical scheme for the first order linear neutral equation x′(t)−γx′(t−τ)=αx(t)+βx(t−τ), with the general initial condition x(t)=φ(t) for −τ≤t≤0. The resulting expression reduces to those previously published for the corresponding retarded equations when γ=0.

In African countries, cancer not only is a growing problem, but also a challenge because available funding and resources are limited. Therefore, African medicinal plants play a significant role in folk medicine and some of them are traditionally used for the treatment of cancer. The high mortality rate and adverse effects associated with cancer treatments have encouraged the search for novel plant-based drugs, thus, some African plants have been studied in recent years as a source of molecules with proven cytotoxicity. This review aims to discuss the cytotoxic activity, in vitro, of African plant crude extracts against cancer cell lines. For the period covered by this review (2017–2021) twenty-three articles were found and analyzed, which included a total of 105 plants, where the main cell lines used were those of breast cancer (MCF-7 and MDA-MBA-231) and colorectal cancer (HCT-116 and Caco-2), which are among the most prevalent cancers in Africa. In these studies, the plant crude extracts were obtained using different solvents, such as ethanol, methanol, or water, with variable results and IC50 values ranging from 200 µg/mL. Water is the preferred solvent for most healers in African countries, however, in some studies, the aqueous extracts were the least potent. Apoptosis and the induction of cell cycle arrest may explain the cytotoxic activity seen in many of the plant extracts studied. Considering that the criteria of cytotoxicity activity for the crude extracts, as established by the American National Cancer Institute (NCI), is an IC50 < 30 μg/mL, we conclude that many extracts from the African flora could be a promising source of cytotoxic agents.

Leishmania microtubules play an important role not only in cell division, but also in keeping the shape of the parasite and motility of its free-living stages. Microtubules result from the self-assembly of alpha and beta tubulins, two phylogenetically conserved and very abundant eukaryotic proteins in kinetoplastids. The colchicine binding domain has inspired the discovery and development of several drugs currently in clinical use against parasites. However, this domain is less conserved in kinetoplastids and may be selectively targeted by new compounds. This report shows the antileishmanial effect of several series of compounds (53), derived from podophyllotoxin (a natural cyclolignan isolated from rhizomes of Podophyllum spp.) and podophyllic aldehyde, on a transgenic, fluorescence-emitting strain of Leishmania infantum. These compounds were tested on both promastigotes and amastigote-infected mouse splenocytes, and in mammalian – mouse non-infected splenocytes and liver HepG2 cells – in order to determine selective indexes of the drugs. Results obtained with podophyllotoxin derivatives showed that the hydroxyl group at position C-7α was a structural requisite to kill the parasites. On regards podophyllic aldehyde, derivatives with C9-aldehyde group integrated into a bicyclic heterostructure displayed more potent antileishmanial effects and were relatively safe for host cells. Docking studies of podophyllotoxin and podophyllic aldehyde derivatives showed that these compounds share a similar pattern of interaction at the colchicine site of Leishmania tubulin, thus pointing to a common mechanism of action. However, the results obtained suggested that despite tubulin is a remarkable target against leishmaniasis, there is a poor correlation between inhibition of tubulin polymerization and antileishmanial effect of many of the compounds tested, fact that points to alternative pathways to kill the parasites. Keywords: Leishmania, Tubulin, DNA-Topoisomerase, Podophyllotoxin, Podophyllic aldehyde

In Western Europe, the HIV-1 epidemic among men who have sex with men (MSM) is dominated by subtype B. However, recently, other genetic forms have been reported to circulate in this population, as evidenced by their grouping in clusters predominantly comprising European individuals. Here we describe four large HIV-1 non-subtype B clusters spreading among MSM in Spain. Samples were collected in 9 regions. A pol fragment was amplified from plasma RNA or blood-extracted DNA. Phylogenetic analyses were performed via maximum likelihood, including database sequences of the same genetic forms as the identified clusters. Times and locations of the most recent common ancestors (MRCA) of clusters were estimated with a Bayesian method. Five large non-subtype B clusters associated with MSM were identified. The largest one, of F1 subtype, was reported previously. The other four were of CRF02_AG (CRF02_1; n = 115) and subtypes A1 (A1_1; n = 66), F1 (F1_3; n = 36), and C (C_7; n = 17). Most individuals belonging to them had been diagnosed of HIV-1 infection in the last 10 years. Each cluster comprised viruses from 3 to 8 Spanish regions and also comprised or was related to viruses from other countries: CRF02_1 comprised a Japanese subcluster and viruses from 8 other countries from Western Europe, Asia, and South America; A1_1 comprised viruses from Portugal, United Kingom, and United States, and was related to the A1 strain circulating in Greece, Albania and Cyprus; F1_3 was related to viruses from Romania; and C_7 comprised viruses from Portugal and was related to a virus from Mozambique. A subcluster within CRF02_1 was associated with heterosexual transmission. Near full-length genomes of each cluster were of uniform genetic form. Times of MRCAs of CRF02_1, A1_1, F1_3, and C_7 were estimated around 1986, 1989, 2013, and 1983, respectively. MRCA locations for CRF02_1 and A1_1 were uncertain (however initial expansions in Spain in Madrid and Vigo, respectively, were estimated) and were most probable in Bilbao, Spain, for F1_3 and Portugal for C_7. These results show that the HIV-1 epidemic among MSM in Spain is becoming increasingly diverse through the expansion of diverse non-subtype B clusters, comprising or related to viruses circulating in other countries.

This investigation is focused on the corrosion evaluation of an as-cast Al-Si alloy, obtained by two different casting methods: traditional sand casting and three-printing casting, using a binder jetted mold. The experimental results are discussed in terms of chemical composition, microstructure, hardness, and corrosion behavior of two different casting parts. The microstructure and composition of the sample before and after the corrosion tests was analyzed using light microscopy (OM), scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDX) and X-ray diffraction (DRX). The corrosion of the two processed castings was analyzed using anodic polarization (PA) test and electrochemical impedance spectroscopy (EIS) in an aerated solution of 3.5% by weight NaCl, similar to the seawater environment. After the corrosion process, the samples were analyzed by inductively coupled plasma/optical emission spectrometry (ICP/OES); the composition was used to determine the chloride solution after immersion times. The sample processed by binder jetting mold showed higher corrosion resistance with nobler potentials, lower corrosion densities, higher polarization resistance, and more stable passive layers than the sample processed by sand casting. This improvement of corrosion resistance could be related to the presence of coarse silicon particles, which decrease of cathodic/anodic ratio and the number of micro-galvanic couples, and the lower amount of intermetallic β Al-Fe-Si phase observed in cast alloy solidified in binder jetting mold.

Betulinic acid (BA, 3β-hydroxy-lup-20(29)-en-28-oic acid) is a pentacyclic triterpene acid present predominantly in Betula ssp. (Betulaceae) and is also widely spread in many species belonging to different plant families. BA presents a wide spectrum of remarkable pharmacological properties, such as cytotoxic, anti-HIV, anti-inflammatory, antidiabetic and antimicrobial activities, including antiprotozoal effects. The present review first describes the sources of BA and discusses the chemical strategies to produce this molecule starting from betulin, its natural precursor. Next, the antiprotozoal properties of BA are briefly discussed and the chemical strategies for the synthesis of analogues displaying antiplasmodial, antileishmanial and antitrypanosomal activities are systematically presented. The antiplasmodial activity described for BA was moderate, nevertheless, some C-3 position acylated analogues showed an improvement of this activity and the hybrid models—with artesunic acid—showed the most interesting properties. Some analogues also presented more intense antileishmanial activities compared with BA, and, in addition to these, heterocycles fused to C-2/C-3 positions and amide derivatives were the most promising analogues. Regarding the antitrypanosomal activity, some interesting antitrypanosomal derivatives were prepared by amide formation at the C-28 carboxylic group of the lupane skeleton. Considering that BA can be produced either by isolation of different plant extracts or by chemical transformation of betulin, easily obtained from Betula ssp., it could be said that BA is a molecule of great interest as a starting material for the synthesis of novel antiprotozoal agents.

Natural products are the ideal basis for the design of novel efficient molecular entities. Podophyllotoxin, a naturally occurring cyclolignan, is an example of natural product which displays a high versatility from a biological activity point of view. Based on its unique chemical structure, different derivatives have been synthesized presenting the original antitumoral properties associated with the compound, i.e., the tubulin polymerization inhibition and arising anti-topoisomerase II activity from structural modifications on the cyclolignan skeleton. In this report, we present a novel conjugate or hybrid which chemically combines both biological activities in one single molecule. Chemical design has been planned based in our lead compound, podophyllic aldehyde, as an inhibitor of tubulin polymerization, and in etoposide, an approved antitumoral drug targeting topoisomerase II. The cytotoxicity and selectivity of the novel synthetized hybrid has been evaluated in several cell lines of different solid tumors. In addition, these dual functional effects of the novel compound have been also evaluated by molecular docking approaches.

In this research, a comparative analysis has been carried out between a traditional sand casting process and a modern mould obtained by additive manufacturing (AM), in the context of aluminium parts production. In this case of AM, an inkjet 3D printing (3DP) process allowed us to create a ceramic mould. A numerical simulation was carried out to study the filling and cooling rates of both parts. The design freedom typical of the 3DP technique allowed us to optimize the filling system. The results showed that in sand moulding, the speed in the gate suddenly increased when the liquid metal entered the part cavity, leading to severe turbulence due to the fountain effect. The input of air is related to the speed in the gate. Nevertheless, the results showed that when using the 3DP mould, the speed in the gate remained constant and the filling process was homogenous. With regard to the dimensional precision, while the staircase effect in the surface of the 3DP mould is the most critical aspect to control, in the sand casting mould the critical aspect is the dimensional precision of the pattern. Microstructures of the cross-section of the moulded parts showed folded shapes and air input in sand casting, which could be produced by the severe turbulence and the oxide film present in the melt during the filling process. On the other hand, the porosity found in parts produced with the 3DP mould corresponds to shrinkage; during the filling process, the remaining binder is vaporized, creating nucleation points. In this way, pores are formed by shrinkage and a mixture of shrinkage and gas entrapment. With these considerations, it can be concluded that AM shows feasibility and advantages as an alternative to the sand casting method for aluminium alloys.

In recent works, exact and nonstandard finite difference schemes for scalar first order linear delay differential equations have been proposed. The aim of the present work is to extend these previous results to systems of coupled delay differential equations X ′ ( t ) = A X ( t ) + B X ( t − τ ) , where X is a vector, and A and B are commuting real matrices, in general not simultaneously diagonalizable. Based on a constructive expression for the exact solution of the vector equation, an exact scheme is obtained, and different nonstandard numerical schemes of increasing order are proposed. Dynamic consistency properties of the new nonstandard schemes are illustrated with numerical examples, and proved for a class of methods.

A recent reinvestigation of aerial parts of Wedelia paludosa D.C. is described and reports, for the first time, the isolation of iso-kaurenoic acid from this species.Uma recente reinvestigação das partes aéreas de Wedelia paludosa D.C. é descrita e relata, pela primeira vez, o isolamento do ácido iso-caurenóico desta espécie.

We recently reported the rapid expansion of an HIV-1 subtype F cluster among men who have sex with men (MSM) in the region of Galicia, Northwest Spain. Here we update this outbreak, analyze near full-length genomes, determine phylogenetic relationships, and estimate its origin. For this study, we used sequences of HIV-1 protease-reverse transcriptase and env V3 region, and for 17 samples, near full-length genome sequences were obtained. Phylogenetic analyses were performed via maximum likelihood. Locations and times of most recent common ancestors were estimated using Bayesian inference. Among samples analyzed by us, 100 HIV-1 F1 subsubtype infections of monophyletic origin were diagnosed in Spain, including 88 in Galicia and 12 in four other regions. Most viruses (n = 90) grouped in a subcluster (Galician subcluster), while 7 from Valladolid (Central Spain) grouped in another subcluster. At least 94 individuals were sexually-infected males and at least 71 were MSM. Seventeen near full-length genomes were uniformly of F1 subsubtype. Through similarity searches and phylogenetic analyses, we identified 18 viruses from four other Western European countries [Switzerland (n = 8), Belgium (n = 5), France (n = 3), and United Kingdom (n = 2)] and one from Brazil, from samples collected in 2005-2011, which branched within the subtype F cluster, outside of both Spanish subclusters, most of them corresponding to recently infected individuals. The most probable geographic origin and age of the Galician subcluster was Ferrol, Northwest Galicia, around 2007, while the Western European cluster probably emerged in Switzerland around 2002. In conclusion, a recently expanded HIV-1 subtype F cluster, the largest non-subtype B cluster reported in Western Europe, continues to spread among MSM in Spain; this cluster is part of a larger cluster with a wide geographic circulation in diverse Western European countries.

Leishmania is the aethiological agent responsible for the visceral leishmaniasis, a serious parasite-borne disease widely spread all over the World. The emergence of resistant strains makes classical treatments less effective; therefore, new and better drugs are necessary. Naphthoquinones are interesting compounds for which many pharmacological properties have been described, including leishmanicidal activity. This work shows the antileishmanial effect of two series of terpenyl-1,4-naphthoquinones (NQ) and 1,4-anthraquinones (AQ) obtained from natural terpenoids, such as myrcene and myrceocommunic acid. They were evaluated both in vitro and ex vivo against the transgenic iRFP-Leishmania infantum strain and also tested on liver HepG2 cells to determine their selectivity indexes. The results indicated that NQ derivatives showed better antileishmanial activity than AQ analogues, and among them, compounds with a diacetylated hydroquinone moiety provided better results than their corresponding quinones. Regarding the terpenic precursor, compounds obtained from the monoterpenoid myrcene displayed good antiparasitic efficiency and low cytotoxicity for mammalian cells, whereas those derived from the diterpenoid showed better antileishmanial activity without selectivity. In order to explore their mechanism of action, all the compounds have been tested as potential inhibitors of Leishmania type IB DNA topoisomerases, but only some compounds that displayed the quinone ring were able to inhibit the recombinant enzyme in vitro. This fact together with the docking studies performed on LTopIB suggested the existence of another mechanism of action, alternative or complementary to LTopIB inhibition. In silico druglikeness and ADME evaluation of the best leishmanicidal compounds has shown good predictable druggability. Keywords: Leishmania infantum, Terpenylquinones, Naphthoquinones, Anthraquinones, Acridinequinone, DNA-Topoisomerase IB