Biomimetic structures are inspired by elegant and complex architectures of natural creatures, drawing inspiration from biological structures to achieve specific functions or improve specific strength and modulus to reduce weight. In particular, the rapid closure of a Venus flytrap leaf is one of the fastest motions in plants, its biomechanics does not rely on muscle tissues to produce rapid shape-changing, which is significant for engineering applications. Composites are ubiquitous in nature and are used for biomimetic design due to their superior overall performance and programmability. Here, we focus on reviewing the most recent progress on biomimetic Venus flytrap structures based on smart composite technology. An overview of the biomechanics of Venus flytrap is first introduced, in order to reveal the underlying mechanisms. The smart composite technology was then discussed by covering mainly the principles and driving mechanics of various types of bistable composite structures, followed by research progress on the smart composite-based biomimetic flytrap structures, with a focus on the bionic strategies in terms of sensing, responding and actuation, as well as the rapid snap-trapping, aiming to enrich the diversities and reveal the fundamentals in order to further advance the multidisciplinary science and technological development into composite bionics. Biomimetic structures are inspired by elegant and complex architectures of natural creatures, which can be lightweight and offer combinations of mechanical properties that often surpass those of their components by orders of magnitude . BiomimeComposite materials have attracted growing interest for their design and manufacturing flexibilities, high specific strength and stiffness, which are superior to reducing structural weight and functional complexities . Smart mThe biomimetic Venus flytrap structures are found mostly by employing the morphing mechanics of smart composites. These contribute to their main characteristics and advantages in terms of (i) structural design freedom, since organisms are variable and complex in nature; (ii) simplicity and lightweight, the conventional deformable bioinspired structure connected by multiple rigid modules through motion pairs is complex and heavy, whilst the shape-changing process of a thin-shelled smart composite is similar to rapid snap-trapping of a Venus flytrap leaf, simplifying the design of biomimetic structures; (iii) energy conservation and flexibility, the smart composite structure stores shapes through binary states, the shape-changing process is reversible without additional input energy, which offers efficient and flexible energy-saving rapid morphing mechanics driven by stored elastic energy.There have been reviews concerning the bionics of the Venus flytrap. The research progress on plant-inspired adaptive structures and materials for morphing and actuation has been reported in , where tVenus flytrap is a magic insect-trapping plant that catches agile insects by the rapid closure of a pair of symmetrical shell-like leaves . When thThe trigger hairs on the inner surface of the flytrap leaves are highly sensitive, see x-direction caused by the biochemical reaction is much larger than that in the y-direction, which is considered to be the actuating factor of the snapping. To dig further into the triggering mechanics of the passive motion at a macroscopic scale, a more detailed bi-layer model has been developed to simulate the internal stress/strain field, see Osmotic driven (active water transport) is crucial for active motion but cannot explain the rapid trapping process of the Venus flytrap. An important reason is that the snap-trap is not caused by the bending of the entire leaves, but a snap-buckling instability through active control . The geoTherefore, the biomechanics of the Venus flytrap consists of two mechanisms: (i) the biochemical reaction through changes in osmotic pressure as explicit sensing and trigger actuation; (ii) the bistable shape transition as the implicit fast trapping motion. Thus, the progress and development of smart composite-based biomimetic flytrap structures are also concentrated on mimicking the smart sensing and actuation strategies, as well as the rapid snap-trapping phenomenon.Smart materials and composite technology are derived from the 1980s. It refers to a material or structural system that is capable of sensing external changes, and responding to stimuli by changing their specific properties, geometric configurations, etc. . They haSmart composites are developed based on smart polymers with improved mechanical performance. Depending on the specific material and structure employed to produce a smart composite, it can be driven by heat , light , magnetiA prelude of smart composite structures also includes those that are bistable, enabling elastic strain energy-based rapid morphing of the biomimetic flytrap. In producing a composite, it is known that thermal residual stress would be generated during cooling, which may lead to deflection, local buckling, and even premature failure of a composite structure in service ,36. AlthThere are mainly two types of bistable composite structures considering the curvature directions of the two stable shapes, namely (i) opposite-sense bistable (OSB) structure, and (ii) equal-sense bistable (ESB) structure, see The thermal residual stress-induced OSB structure is the most established, which is produced by employing unsymmetric composite layups. A typical example is shown in Plants that harvest energy from nature through photosynthesis accomplish perception and response to changing conditions without brain control. They provide possibilities for constructing advanced biomimetic structures that rely on adaptive material systems without control centers. The sense and response of a material system to changing environmental conditions are related to the corresponding biological reaction mechanisms. Therefore, plant-inspired biomimetic structures have focused on the achievement of plant functional principles, rather than simply imitating the behavior of plant movement in past decades . These bThe function of sensing for biomimetic flytrap structure is usually achieved by integrating smart material-based sensors. To date, the sensing characteristics of ionic polymer metal composites (IPMCs) are the most popular to mimic the trigger hairs of flytrap leaves. IPMC is an intelligent material superior in terms of bidirectional motion, fast response, and low driving voltage. When it is bent by an external force, the solvent is replaced, and the resulting charge polarisation generates a voltage on both sides of the material. Based on this acting principle, the IPMC has been applied to mimetic the trigger hairs, i.e., bending sensor. Under the influence of an external electric field, the redistribution of water molecules in IPMC leads to its bending deformation, involving a series of energy conversions, including electrical energy, chemical energy and mechanical energy.The sensing characteristics and mechanical bending of an IPMC system are similar to the sensing and actuation of the flytrap. The sensing function of biomimetic structures is often achieved by using stimulus-responsive materials, which are sensitive to changes in environmental conditions and deformed accordingly. A notable feature of hydrogels is that their volume changes during a wide range of environmental conditions. However, the leaves of a flytrap can quickly close within a tenth of a second to catch insects, significantly different from the usual slow shape transition of hydrogels. Therefore, the ingenious combination of sensing external stimuli and improving responsive speed needs to be implemented in hydrogel-based biomimetic designs. It is worth noting that soft materials in nature are inhomogeneous. They have multiple functional regions with different chemical and mechanical compositions. Therefore, the composition and distribution of different materials could also be learned for biomimetic response structural systems. Another concept of snap-trap based on the rGO/PDMAEMA composite hydrogel sheet is shown in A pure humidity-responsive artificial flytrap leaf is shown in Compared with the above hydrogel-based driving systems that can only perceive and react in a liquid environment, light-driven smart material has lower environmental requirements. The biomimetic strategies stated above mostly rely on the sensing capability to initiate snap-trapping. They lack elastic deformation-induced actuation, and the smart responses are usually in slow motion. Integration of the sensing capability into a bistable system may be more suitable for the biomechanics of the flytrap structure. The flytrap leaf is regarded as an elastic irregular curved shape. The macroscopic response of the flytrap after sensing the prey is that the leaves deform and pass through the energy barrier, and the stored elastic energy is instantly released and converted into kinetic energy, thereby forming a rapid snap-trapping action . To dateTherefore, the morphing process of an OSB- or ESB-based bistable structure can be designed to introduce elastic energy-driven mechanisms into the flytrap structure. In addition, attempts have also been explored by using ESB-based structures, which also depict the real curvature changes of the flytrap leaves. Although the shape-changing characteristics of the bistable artificial leaves are similar to those of the real flytrap leaves, the internal stress field of the real flytrap leaf is locally orthotropic and follows the geometric shape of the leaf as a whole, see details as discussed in A further strategy is considering multiple driving methods to mimic the biomechanics of the flytrap. The biggest challenge for future smart composite bionics is to create a biomimetic flytrap structure that can pass the Turing test, which is designed to assess whether a model can accurately mimic the properties of a biological system. This means that a biomimetic structure is able to grow, and recover, and also has similar sense and response capabilities to that of a real Venus flytrap. Although some investigations have proposed self-growing robot concepts, the current biomimetic structures for flytraps still remain at the initial quickly growing stage. Therefore, this review focuses on the bionic strategies in terms of sensing, responding and actuation, as well as the rapid snap-trapping of the biomimetic Venus flytrap structures by employing the smart composite technology, aiming to enrich the diversities and reveal the fundamentals in order to further advance the multidisciplinary science and technological development into composite bionics.The in-depth analysis of the biomechanics of a real Venus flytrap is helpful and essential in order to further promote and advance biomimetic structures. Flytrap leaves are not fully folded when stones, raindrops, etc., come into contact with trigger hairs, but only when prey is getting in contact. This energy-saving mechanism is still magical and worth further investigation. By using a multi-stable structure or driving control strategy, a multifunctional fly-catching biomimetic structure may be achieved. Compared with the enclosed trapping of the real flytrap, it is more realistic to mimic the bending or clamping motion for smart composite-based flytrap structures, and their driving strategies are diverse. The precision control of the express snapping and the load output range are still limited and depend on further development into smart composite technology. The sensing characteristics of IPMC are most similar to those of flytraps; whilst it lacks the elastic energy-derived rapid snapping. IPMC is promising to be applied as an actuator in the future owing to its sensing and fast response capabilities, in order to trigger the bistable artificial leaves. An exciting solution is a programmable microstructural bistable composite with multi-stimuli and multi-temporal responsive mechanics. The combination of bistability and bionics provides a new concept for developing the biomimetic structure with rapid shape morphing capability. In particular, the bistable composite structures offer similar shape-changing characteristics to a real flytrap leaf, and the elastic energy-driven actuation enables rapid capture motion. In the meantime, imitating the real curvature changes and internal stress field of a flytrap leaf improves the capture effectiveness of the biomimetic flytrap structure.


Plasmodium falciparum. Driven through a multitude of virulence factors, varied immune responses, variations in brain swelling with regard to the age of patients, parasite biomass, and parasite-typing, the essential pathogenetic mechanisms underlying clinical CM have remained elusive. However, a recent series of studies based on molecular, immunologic, and advanced neuroradiologic and machine-learning approaches have unraveled new trends and insights to better understand and focus on the key determinants of CM in humans. This could possibly be the beginning of the design of new and effective adjunctive therapies that may not be common or applicable to the entire malarious world, but that could, rather, be specific to the variations in the determinants of CM.No specific or adjunctive therapies exist to treat cerebral malaria (CM) as of date. CM is a neuropathological manifestation of the malaria infection in humans, caused by the hemoparasitic pathogen  Plasmodium falciparum amongst the other species of Plasmodia that infect humans. The inability to treat cerebral malaria in humans is primarily due to the lack of a specific anti-CM drug or an adjuvant. Considering the multifactorial nature of the neuropathology in cerebral malaria, even the most potent antimalarials [Malaria is a major public health menace in the tropical and sub-tropical regions of the world, with an estimation of 247 million infections and 619,000 human deaths occurring from severe complications in 2021 [alarials  fail to Cerebral malaria is the neuropathological manifestation of malaria, effectively constituted through contributions from the parasite and the human host ,4. The pThe detailed pathophysiology leading to the development of CM and brain injury remains an enigma. However, major postulations pointed to the sequestration theory that cytoadherence of the parasitized red blood cells (pRBCs) on to the endothelial cells, facilitated by rosette formation in the cerebral microcapillaries, causes brain ischemia, and the resulting immune-inflammatory responses lead to the concurrent onslaught on the blood-brain-barrier (BBB) by a cytokine storm and reactive oxygen species ,12,13,14var gene transcripts as well as higher levels of parasite biomass [var gene transcripts (EPCR binders) in CM patients from Rourkela, eastern India, was found to be consistent with an earlier study on severe adult malaria patients from Goa, western India [A series of recently demonstrated findings on CM patients from India and Africa using magnetic resonance imaging (MRI) based neuro-radiological studies started shedding light on several grey areas and widened the horizon to better understand the key pathogenetic mechanisms of action during the development of CM. For example, in a subset of non-fatal CM patients from India, following standard treatment, the increase in brain volumes was found to be caused by vascular engorgement and reversible impairment of BBB through posterior reversible encephalopathy syndrome—PRES . Consist biomass . In thisrn India . Subsequrn India .var transcripts-binding phenotypes [In the past few decades, an array of tools, models, and biomarkers have been identified to better understand the pathogenesis of severe and cerebral malaria, and many candidate adjuvants have been proposed with different mechanisms of action and promising the potential to treat CM . Despiteenotypes , varyingenotypes ,21,22, aenotypes . Therefoenotypes  and promenotypes  respectienotypes  in experenotypes  and the enotypes . Besidesenotypes . These nIn view of the recent trends and the new insights gained from molecular, immunological, and neuroradiological approaches to understand CM pathogenesis, it is now evident that a common adjunctive therapeutic for CM will not be effective across the whole of the malarious world, and especially for adults and children . Moreove


Applications of DNA-containing nanomaterials (DNA-NMs) in science and technology are currently attracting increasing attention in the fields of medicine, environment, engineering, etc. Such objects have become important for various branches of science and industries due to their outstanding characteristics such as small size, high controllability, clustering actions, and strong permeability. For these reasons, DNA-NMs deserve a review with respect to their recent advancements. On the other hand, precise cluster control, targeted drug distribution in vivo, and cellular micro-nano operation remain as problems. This review summarizes the recent progress in DNA-NMs and their crossover and integration into multiple disciplines . We hope that this review will motivate relevant practitioners to generate new research perspectives and boost the advancement of nanomanipulation. The multidisciplinary scientific topic of DNA-NMs applications gained popularity in the last century when the use of DNA as a building material was shown to be both brilliant and straightforward. Nearly 40 years of productive effort have solidified the underlying theories of the field and have widened previously unimaginable paths such that now, DNA objects of nearly any desired size and form can be quickly created. More importantly, they can be created with spatial control at the nanoscale level . These eOver the last ten years, a variety of biological applications have made extensive use of the manipulation and characterization of biological cells based on this technique, including cell transfer, isolation, immobilization, and injection . Micro/nDNA-NMs have been created and customized to achieve a variety of biomedical applications because of their inherent dynamics and biocompatibility. Several DNA nanodevices have so far been successfully created for performing a wide range of jobs, including sensing tasks and information processing in a biological context, the quantitative imaging of analytes in live cells , and disAs indicated in The programmable performance of nanosystems, which are researched for biomedical applications, is useful for the design and development of medicines that take patient profiles into account, i.e., individualized health management ,20, in aVarious scientific research fields for assembling and synthesizing materials, such as synthetic chemistry , supramoThe nanoarchitectonics concept is supposed to involve the architecting of functional materials using nanoscale units based on the principles of nanotechnology. The production of functional materials via nanoarchitectonics approaches is done through the combination and selection of several unit processes, including molecular synthesis, atom/molecular manipulation, self-assembly/self-organization, field-applied assembly, micro-fabrication, and bio-related processes . Since tThe need for fresh views on in vivo-like and animal-free methodologies for chemical and pharmaceutical safety evaluation is expanding both in drug development and chemical risk assessment .Enzymatic catalysis has used scaffolds as reactors. Potential reaction cascades are made possible by these materials’ facilitation of the regulation and improvement of catalyzed reactions under the control of the nanoparticle, enzyme nanoreactors allow researchers to control how much an enzyme can catalyze, as opposed to traditional homogeneous experiments in solution. This method improves the stability and activity of enzymes, enabling the use of enzymatic processes in novel environments . AdditioThe first immobile Holliday junction, which consists of four different strands entwined at a single crossing point, was designed and published by Nadrian Seeman in 1982 . A few ySeveral years after the foundation of DNA nanotechnology, a different self-assembling technique was created and eventually dubbed scaffolded DNA origami . The funDNA-NMs that involve proteins : from the synthesis of DNA-tagged proteins (herein referred to as DNA–protein conjugates) until their integration onto substantial DNA scaffolds (resulting in what is herein referred to as DNA–protein nanostructures or NMs), with a focus on their binding affinity and catalytic activity. The development of a homogeneous chemical species with a high purity grade is the first essential step in the study of such hybrid materials. Only then can any observable change in the biophysical characteristics of the DNA–protein (enzyme) nanostructure be linked to a specific structural characteristic of the sample .So far, several strategies have been created and are being continuously improved to allow the binding of a protein of interest to a DNA molecule. For creating DNA–protein hybrids, either natural proteins or their genetically modified variations are employed as starting points for chemical conjugation, enzymatic ligation, or a combination of the two. The power and selectivity of the newly created interaction serve as a simple means of categorizing these tactics. It has been proposed that the option of the DNA–protein (enzyme) contact be either covalent, which would be primarily strong and irreversible, or non-covalent, which would be weaker and more readily dissociable. Moreover, the newly created bond may address several sites that are chemically equivalent and physically indistinguishable, or it may only address one specific site of the proteins of interest (POI) ,48.The recent finding that single-stranded DNA (ssDNA) and CNTs may be assembled in a sequence-dependent manner has spurred the development of methods for generating long strands of ssDNA (>100 nt) with high yield and homogeneity. Small repetitive DNA sequences have drawn more attention due to their potential applications in nanotechnology as well as the fact that the presence of these repeats often leads to genomic instability in organisms . Twelve NMs are distinctive from bulk materials because of their adjustable and distinctive physical, chemical, and biological characteristics. Chemical and nanotechnology might be researched in a cooperative, synergistic way due to their comparable aims and toolkits. Artificial nanomaterials can affect biological functions on living cells’ surfaces, inside them, and even in certain intracellular compartments. A wide range of exploratory areas, including chemical-, cell-, and mechanobiology, have been made possible by size, physicochemical control, and ensuing biological interactions with nanomaterials. Inorganic to biodegradable polymers, among other wide groups of nanomaterials, have been created for molecular transport, enzymatic catalysis, molecular imaging, and molecular sensing. Numerous uses of nanomaterials have also entered the clinic .DNA has developed into a new, multi-disciplinary area that combines elements of chemistry, biology, biomedicine, and materials science . CompareShort oligonucleotides known as aptamers are selected from a large nucleic acid library using the SELEX method based on their affinity to target cargos ,78,79,80Cell-SELEX, a cutting-edge method created in 2006 by Tan’s team, enables the selection of aptamers against target living cells without the need to be aware of the chemical fingerprints on the cellular membrane ,91. BaseThe majority of techniques for creating aptamer-integrated DNA-NMs are based on nucleic acid hybridization. Since DNA-NMs are highly programmable and adhere to the rigorous Watson–Crick pairing requirements, aptamers may be added site specifically to provide customized capabilities. This can be accomplished either by post-functionalization or the DNA nanostructure construction technique. For instance, aptamer-modified staples were one of the building pieces used by Tanner and colleagues  to constDNA-NMs are appealing drug delivery vehicles due to their biocompatibility, biodegradability, and nontoxicity ,112, and2+, are necessary for structural stability to prevent DN denaturation. When compared to physiological fluids like human serum, which typically contains 1 mM of divalent cations, these concentrations are about an order of magnitude greater [The dense packing of DNA helices required for the self-assembly of DNA-NMs frequently causes electrostatic repulsion between the negatively charged phosphate backbones of the DNA helices. High concentrations (5–20 mM) of divalent cations, such as Mg greater . Further greater ,117.It is crucial to monitor and control chemicals in organisms in real time at the molecular level. Because of this, in situ target biomolecule analysis has enormous promise for physiology and medical research. Through DNA sequence coding, the decades-old DNA nanotechnology developed by Seeman opens new opportunities for the synthesis and creation of synthetic DNA-NMs in vitro . DNA nanIn addition to structures obtained in Seeman’s lab, there are some other recently developed structures worth mentioning, in particular, if employing polycations to assist the shaping.By complexation of plasmid DNA by PEG-polycationic block copolymers, its self-assembly results in either toroidal structures, rod structures, or globular structures. The outcome depends on salt concentration and strandedness of DNA, e.g., the complexation of dsDNA with PEG-polycation in 600 mM NaCl forms toroidal structures. Without salt, the same dsDNA forms rod-shaped structures. Compared to the rod-like structure, the toroidal structure has better biological functions that can not only increase transcription in vitro but also increase the efficiency of gene transduction in vivo. This demonstrated the great usefulness of toroidal packing of plasmid DNA as a separate structured carrier of genes . The expThe simplicity of manipulation of polymer micelles makes it possible to adjust important parameters necessary for the protection of NA and effective delivery to the target sites. The ordered core–shell structure allows the inclusion of other therapeutic/diagnostic agents, providing an opportunity for combined therapy and theranostics .By self-assembly of DNA structures, most DNA hydrogels are formed. Self-assembly can occur in a polymer matrix to build an interpenetrating network (IPN) hydrogel. The study of the mechanism shows that self-assembly between short chains of ssDNA leads to the formation of long linear DNA parts and loop structures, and entanglement between these DNA assemblies at high concentrations leads to the formation of three-dimensional hydrogel networks. By programming the sequence of the ssDNA chain, it is possible to construct a pH-sensitive DNA hydrogel or a catalytic DNA hydrogel . ProgramPolyhedral DNA-NMs consisting of three- or four-branched branches connected by rigid ribs in the form of a double helix can be constructed using self-assembly protocols that use the specificity of base pairing interactions. The DNA tetrahedron was the first such structure to be created quickly and with high yield from multiple chains in a single assembly step. The bipyramid contains three four-shoulder and two three-shoulder joints; all its faces are triangles, so the design must be rigid. Easy and efficient synthesis is a necessary step toward using these controlled three-dimensional frameworks as building blocks for functional molecular cell construction .As mentioned above, DNA-NMs are of great interest mostly because such hybrid materials combine the molecular recognition and programmability of DNA with the physical properties of organic or inorganic nanoparticles, demonstrating promising applications in many fields, including biosensing, drug delivery, materials science, and nanotechnology. Over the past two decades, many nanomaterials such as metal nanoparticles, semiconductor quantum dots, and nanoscale carbon materials such as carbon nanotubes (CNT) and graphene oxide have been modified by DNA.The key step in creating such materials is the attachment of DNA to the surface of the particles. While covalent attachment provides a strong bond with DNA, physical sorption is attractive for its simplicity, cost-effectiveness, and reversible binding .Understanding the processes of adsorption and desorption is necessary for the optimization of DNA microarrays, the development of biosensors, and the functionalization of nanoparticles. Therefore, the interaction of DNA with inorganic surfaces aroused great research interest . AdsorptThere are two main differences between ssDNA and dsDNA in the context of their interaction with AuNP. Firstly, heterocyclic bases of ssDNA, being spatially accessible, are capable of forming hydrogen bonds and/or hydrophobic contacts with atoms on the surface of the AuNP; these processes are very difficult for heterocycles inside dsDNA. According to a number of studies, it is this interaction that determines the binding strength of NA with AuNP. The second difference is that ssDNA has a much more mobile structure, whereas dsDNA has a rigid structure that prevents direct interaction of nitrogenous bases with the surface of nanoparticles .ssDNA can be adsorbed by AuNP. Coating nanoparticles with citrate leads to an increase in the stability of AuNP. Studies have shown that the adsorption capacity of DNA is determined by the length of the DNA oligomer and the concentration of DNA and salt since both DNA and AuNP have the same charge in aqueous solutions . DNA adsAuNPs, functionalized with DNA, are widely used for targeted assembly of materials, biosensors, and drug delivery. All four DNA bases can be strongly adsorbed on gold due to coordination interactions, and therefore even non-isolated DNA can be attached to AuNP .Nucleic acids must self-assemble to support many of the fundamental biological activities in living things. The storing and programmed execution of instructions stored in a DNA sequence are key aspects of this self-assembly process . It is iMicrocircles, a prokaryotic vector component made up of one active transcriptional unit plus an attachment region to the matrix (S/MAR), are described as the result of parental construct optimization. Some changes still exist, but this name is still used to refer to vectors with a comparable function  Figure . Such veWhen Zheng et al. presented the hybridization of single-stranded DNA (ssDNA) and single-walled CNTs (SWNTs) in 2003, it was the first time that DNA and CNTs have been reported to interact . In addiSince 2003, two primary hybridization research objectives have been established. Enhancing CNTs’ solubility is the first step. Uncoated CNTs often form insoluble bundles in aqueous solutions, even though their distinctive structural and physicochemical features make them intriguing for both basic research and commercial applications. CNTs need to be produced in a mono-dispersed state to maximize their potential, and this is particularly true for SWNTs. Mono-dispersed CNTs can be made by attaching hydrophilic organic molecules, which can improve CNT solubility. Examples of these molecules include sodium dodecyl sulfate (SDS), peptides, proteins, and DNA molecules.When biomaterials  are combined with CNTs, new hybrid systems are created that combine the conductive or semiconductive capabilities of CNTs with the catalytic or recognition abilities of the biomaterials. New bioelectronic systems, such as biosensors and field-effect transistors, or nanocircuitry that is templated, may result from this. The development of this research area involves a variety of difficult problems, including the synthesis of site-specific and structurally defined biomaterial–CNT hybrids, enhanced techniques for the separation and characterization of conductive and semiconductive CNTs, the ordered and controlled assembly of addressable biomaterial–CNT systems on surfaces, and the creation of microscopic imaging methods to characterize the structures and functions of the nanoscale devices .The DNA origami technique makes it possible to form arbitrary, precise, and complex two- and three-dimensional nano-objects with specified rotations, curvature, and tension. Traditionally, origami is formed by folding a skeleton thread, that is, a long ssDNA, into the desired shape using a predefined set of oligonucleotides, but constructions without frameworks are also possible .Employment of DNA origami nanostructures as platforms for binding and assembly, it is possible to achieve control over the shape, size, and topology of the viral capsid. The latter can have different geometries, most clearly characterized by icosahedral or spiral symmetry. It is important to note that precise control over the size and shape of viral capsids will be important when developing new vaccines and delivery systems. In addition, the resulting viral capsid coatings can protect encapsulated DNA origami from degradation .The transfection efficiency could be gradually increased with increasing concentration to a level at which the DNA origami was completely covered with capsid proteins. Complete encapsulation makes it possible to deliver multiple functionalized DNA origami to cells and, thus, use programmable combinations of specific drugs for achievable medical procedures. In the future, the organization of reactions inside the cell can be realized with the help of modular docking nodes on origami .Finally, it is worth mentioning spherical nucleic acids, which are structures composed of chemically modified inorganic nanoparticles in the nucleus and a dense layer of highly organized thiol-modified oligonucleotides as a shell, which are chemically bound to the surface of the nucleus through thiol bonds. Oligonucleotides provide a negative charge and increased colloidal stability, steric stabilization in solutions with increased ionic strength, and the ability to combine with other biomolecules for molecular visualization or drug delivery .The developed antiviral SNA vaccine with the employment of spherical NA induces the formation of memory B cells in human cells. Its administration to mice in vivo creates stable binding and neutralizing antibody titers, mice that received the SNA vaccine had a 100% survival rate and lungs that were free of the virus by plaque analysis .The stability of DNA nanostructures should be improved with great care. It is also necessary to develop techniques for examining the stability of DNA nanostructures in vivo. It is known that unprotected DNA experiences degradation in vivo .It is necessary to make it easier to manipulate ligands on DNA nanostructures, increasing the efficiency of DNA–ligand conjugation and identifying the distribution of receptors on the cell surface. The creation of ligand-conjugated DNA nanostructures requires the development of effective preparation methods.It is important to assess the in vivo pharmacodynamics and pharmacokinetics of ligand-functionalized DNA nanostructures. The application of therapeutic ligand modification on DNA nanostructures is common. Nonetheless, in vitro research is the main emphasis of the effort.DNA is one of the most advantageous nanotechnology materials. It can self-assemble, build programmable nanostructures, act as a platform for mechanical, chemical, and physical devices, and have the ability to self-assemble. Even though nature has evolved many intricate nanoscale systems over thousands of years, scientists and engineers must work hard to create new technologies that will enable the use of DNA in more fields, including physics, medicine, computing, and material sciences. Nanotechnology must be enhanced to fulfill the need for better detectors in the sectors of biological and chemical detection as well as for higher sensitivity. More efforts are necessary for the further development of ligands functionalized DNA NM, even if nano–DNA manipulation has demonstrated potential qualities for targeted treatment and diagnosis:One of the most promising platforms for the modification of ligands to support the advancement of precision medicine is DNA nanotechnology.


Biogenic volatile organic compounds (BVOCs) are secondary metabolites which play an important role in the adaptive capacity of trees in response to climate change. BVOCs released into the atmosphere, including isoprene, monoterpenes, sesquiterpenes, and their oxygenated derivatives, are shaping the oxidative capacity of the atmosphere, particularly within forested regions , thus coBVOC emissions are involved in defense mechanisms against biotic stresses, such as herbivores and parasites, acting both as allelochemicals and as as signals to neighboring plants . They plBiogenic Volatiles in Natural and Urban Forest” comprises one review article and four research papers.The Research Topic “Mu et al. conducted an in-depth analysis of the spatial and temporal fluctuations of these emissions. It is emphasized on the regional variability and species specificity of the biogenic emissions.The blend of BVOCs is species-specific and constitutes a metabolic fingerprint than can be deciphered through volatilomic screening . The amoMoura et al. who investigated the effect of ozone (O3) on three native species from the Atlantic Rain Forest: Croton floribundus, Astronium graveolens and Piptadenia gonoacantha. By combining measurements of BVOC emissions and histochemical techniques, the authors aimed to reveal the strategies of these species to counteract oxidative stress. Moreover, the authors discussed the interaction of BVOCs emissions with the atmospheric chemistry, particularly within the formation of tropospheric O3, which in turn could stimulate further BVOCs emissions.The emission of BVOCs from tropical plants is also the topic of the paper of Tullus et al. investigated the effects of competitive status, within-crown light environment, and climate on the secondary chemistry of Betula pendula. The investigation conducted by the researchers revealed notable fluctuations in the composition and profile of secondary metabolites, primarily related to phenolic defense compounds and growth regulators, in response to climatic factors. These variations align with the trees’ adaptive defense mechanisms against herbivory, exposure to irradiance, and competitive status in terms of resource availability. Furthermore, the metabolic profile exhibited by the fine roots not only corresponds to defense requirements, but also signifies distinct below-ground competition strategies in warmer and colder climates.Since the emission of BVOCs also varies on the basis of the microclimatic conditions, Effah et al. investigated BVOCs emission pattern of the shrub Dracophyllum subulatum, a species native in the Central Plateau of the North Island, New Zealand, emphasizing on the relationship between emissions induced by biotic and abiotic factors. Fitzky et al. aimed to provide insights into the species-specific stress tolerance potential of seedlings of four broadleaf tree species: Quercus robur, Fagus sylvatica, Betula pendula, and Carpinus betulus. This study shows that the emissions of specific BVOCs are highly interrelated and can be considered the first step in linking the metabolism and function of co-occurring BVOCs emissions.Finally, two studies investigated the constitutive emissions of plants. In conclusion, the papers published combine a series of new valuable information for readers in the field of BVOC emissions - atmospheric chemistry interactions, as well as the fluctuations in secondary metabolites and their adaptive defense mechanisms in response to climatic factors. Additional studies on emission patterns under stress conditions will be of utmost significance to better understand plant-environmental interactions in the face of intensifying climate change. In addition, owing to high air pollution concentrations, prospective changes in BVOC emission blends in urban areas merit special consideration.All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.


Malignant tumors remain one of the main sources of morbidity and mortality around the world. A chemotherapeutic approach to cancer treatment poses a multitude of challenges, primarily due to the low selectivity and genotoxicity of the majority of chemotherapeutic drugs currently used in the clinical practice, often leading to treatment-induced tumors formation. Highly selective antitumor drugs can largely resolve this issue, but their high selectivity leads to significant drawbacks due to the intrinsic tumor heterogeneity. In contrast, plant polyphenols can simultaneously affect many processes that are involved in the acquiring and maintaining of hallmark properties of malignant cells, and their toxic dose is typically much higher than the therapeutic one. In the present work we describe the mechanisms of the action of polyphenols on cancer cells, including their effects on genetic and epigenetic instability, tumor-promoting inflammation, and altered microbiota. Later decades confirmed the applicability of this concept [5. Cancer-enabling characteristics, such as genetic and epigenetic instability, chronic inflammation, and altered microbiota, do not comprise malignant phenotype per se, but they may accompany the entire process of tumorigenesis, facilitating malignant transformation.Malignant tumors are among the longest-known diseases in the mankind history . The mos concept , and theAcquiring all of these properties requires many large-scale changes in cellular physiology and genetics, which, with the exception of rare cases of chromotrypsis , cannot Processes responsible for the development of a malignant tumor are controlled by a small set of mutations for only a limited period of time. During the rest of the malignant transformation, its progression is driven by a broad spectrum of factors that simultaneously affect a multitude of cellular components and processes. At the same time, a number of anticancer drugs that are currently used and developed are characterized by a high specificity to their targets, and, although these drugs are able to slow tumor growth or even cause a significant reduction in its volume, their efficiency decreases drastically during long-term use. Such a decrease is caused by intra-tumor genetic heterogeneity, as the small number of malignant cells that are insensitive to the selected drug already exist within the tumor at the beginning of the therapy. Even a combination of several highly specific anticancer drugs cannot always prevent the emergence of this effect. Development of anticancer drugs with multiple molecular targets was proposed in order to overcome this drawback ,15. AnotOne approach to reduce the cancer-caused mortality is to prevent the development of a malignancy rather than trying to cure it. It is established that around 45% of cancer cases are preventable . The mosCell-intrinsic processes might also be the cause of cellular DNA damage. Aside from mistakes made by replicative DNA polymerase during each S-period, there are also a multitude of sources of highly reactive compounds within the cells, such as reactive oxygen species . To effeWhen discussing anticancer chemotherapeutic and chemopreventive drugs, their cost is also a concern. Indeed, the annual cost of a chemotherapeutic anticancer drug may be as high as USD 100,000 annually . For cheIn summary, duration and mechanism of malignant transformation dictate a long list of requirements for a potential anticancer or chemopreventive drug: it should be highly specific towards tumor cells while having low or no toxicity, a broad spectrum of intra-cellular targets in a tumor, and high cost efficiency. At the first glance, these requirements cannot be achieved simultaneously. However, during the past decade, a dependence of cancer morbidity on diet was discovered: for individuals whose diet included a large amount of plant-based food, the incidence of cancer was lowered. Subsequent studies established that the main factor responsible for this correlation was the enrichment of dietary substances with plant polyphenols . These cOne of the most prominent features of plant biochemistry, which is almost completely absent in the animal kingdom, is the ability of plants to synthesize a broad spectrum of small organic molecules of multiple different structures, which are collectively known as plant secondary metabolites . More thPolyphenolic compounds can be found in large quantities in fruits, seeds, and other edible parts of plants ,33. FruiAs malignant transformation includes several stages and requires a long period of time to be completed , decreasConfirmation of the anticancer and chemopreventive properties of polyphenols brought forth a question about the exact molecular mechanisms that underlie these activities. Unlike many other clinically used plant secondary metabolites that can interact with a limited number of molecular targets, or even with only a single one, plant phenolic compounds are able to interact with a broad spectrum of biological macromolecules of several different classes . It was Evidence of the biological activity of plant phenolic compounds accumulated to date, combined with data regarding their interaction with cellular targets, makes it possible to consider these substances as a basis for the development of perspective anticancer and chemopreventive drugs. Nevertheless, mostly non-specific binding of polyphenols to their molecular targets and a broad range of these targets make it necessary to extensively study the influence of polyphenols on regulatory pathways and processes involved in tumorigenesis and the development of cancer-enabling characteristics.Human cells are exposed to a wide variety of DNA-damaging substances, both exogenous and endogenous, which include polycyclic aromatic hydrocarbons , polycycMechanisms of modulation of AhR activity by polyphenols are not limited to direct competitive inhibition or agonism . PhenoliThe most important proteins, the expression of which is regulated by the AhR signaling pathway, are several proteins of the cytochrome P450 family. The human genome contains more than 50 genes of these redox enzymes. These enzymes participate not only in xenobiotic activation, but also in fatty acid and cholesterol biosynthesis, the metabolism of steroid hormones and vitamins, and unsaturated fatty acid oxidation . ReactioPlant polyphenols are not only able to prevent DNA damage, but also facilitate their detection and repair. For example, treatment with natural phenolic compounds might affect expression of the γH2AX histone variant that marks double-stranded DNA breaks in interphase chromatin, thus leading either to repair of these breaks  or to seOrganic and inorganic free radicals are other important classes of DNA-damaging substances ,116. ThePlant polyphenols can mitigate the oxidative stress not only by free radical scavenging, but also by preventing their formation. It was established that phenolic compounds can act as chelators of metal ions, thus decreasing the rate of free radical formation catalyzed by these ions. This kind of activity was demonstrated for flavonoids  and for Despite the significant amount of evidence of the antioxidant activity of plant polyphenols obtained during the experiments with cell-free extracts, cell cultures, and in vivo studies, the influence of natural phenolic compounds on the cellular redox status turned out to be more complex, and even prooxidant . PolypheAntioxidant activity of plant phenolic compounds is not limited to direct radical scavenging. Polyphenols can also affect the redox status of the cell by attenuating metabolic processes involved in the generation and neutralization of free radicals. Nrf2 is one of the most important transcription factors responsible for activation of the expression of oxidative stress response proteins. Oxidative stress induces dissociation of the Keap1-Nrf2 complex, preventing its Keap1 ubiquitination-induced proteasomal degradation, and thus leading to an accumulation of active Nrf2 and to the activation of the transcription of Nrf2-regulated genes . It was Plant polyphenols can also modulate the activity of other proteins involved in the maintenance of the cellular redox status. Green tea polyphenols have an inhibitory activity towards expression of NADPH oxidase subunits, thus attenuating production of reactive oxygen species. The ability of EGCG and theaflavin-3,3′-digallate to inhibit lipopolysaccharide (LPS)-induced induction of inducible nitric oxide synthase (iNOS) expression was also established ,142.When considering the antioxidant activity of polyphenols for anticancer and chemopreventive applications, it should be kept in mind that reactive oxygen species are involved in regulation of a number of cellular processes, and in turn, are subjected to strict regulation . There iDNA damage imposed by different factors affects the expression and functions of cellular proteins in a straightforward manner—by changing DNA sequence and thus affecting activity of the encoded proteins or misregulating their expression. However, the activity of the regulatory elements of the cellular genome is regulated not only by DNA sequence, but also by a number of non-genomic hereditable markers, commonly known as epigenetic factors. These factors include methylation of DNA, methylation, acetylation, and other post-translational modifications of histones, histone variants incorporated into chromatin, and non-coding RNAs . It was Plant phenolic compounds affect a multitude of cellular processes involved in epigenetic regulation. EGCG might attenuate activity of DNMT DNA methyltransferases by downregulating their expression , and by Plant polyphenols can also modulate activity of proteins involved in the epigenetic modification of histones in tumor cells. It was established that treatment of LNCaP  prostateEpigenetic mechanisms can regulate the expression of cellular genes both at the stage of their transcription and by changing the amount or activity of its mRNA. The key components of these regulatory systems are non-coding RNAs (ncRNA) known as microRNAs (miRNAs), capable of inhibiting translation of mRNAs or promoting their degradation . There iMany plant polyphenols can modulate expression of ncRNA, thus affecting their regulatory activity. It was established that treatment of HepG2 human hepatocellular carcinoma cell culture with EGCG downregulated the expression of 48 different miRNAs, while upregulating expression of another 13 miRNAs at the same time. Upregulated miRNAs included miR-16, which targets mRNA encoding Bcl-2 antiapoptotic protein, causing suppression of the proliferation and induction of apoptosis . TreatmeCurcumin also modulates miRNA expression. In a recent study, the ability of this polyphenol to induce global changes in mRNA and miRNA expression in MCF-7, MDA-MB-321, and T47D human breast cancer cell cultures was established; the exact pattern of changes in RNA expression was individual for each cell line . DownregModulation of miRNA expression in several cancer cell lines that led to inhibition of the proliferation and induction of apoptosis was also demonstrated for quercitin. Treatment with this polyphenol upregulated expression of miR-16 in HSC-6 and SSC-9 human oral cavity squamous cell carcinoma cell cultures, leading to inhibition of proliferation ; similarResveratrol also causes modulatory activity towards miRNA expression in tumor cells. It was demonstrated that treatment of murine C6 glioma cell cultures and xenografts with this phenolic compound downregulated expression of miR-21, miR-30a-5p, and miR19, leading to global changes in cellular proteome and inhibition of proliferative activity . AntiproGenistein also has modulatory activity towards miRNA expression. Treatment of human C918 uveal melanoma C918  and SKOVA significant amount of data on the modulatory activity of natural polyphenols and on multiple mechanisms of epigenetic regulation were accumulated to the present day, allowing for the possible development of anticancer and chemopreventive drugs that may utilize this activity to prevent or reverse cancer-associated epigenetic disorders. The list of plant polyphenolic compounds that are known to modulate epigenetic regulation systems is not limited to the compounds described above, and is expanding rapidly . The abiInflammation is a complex response of innate and acquired components of the immune system after a traumatic or infective injury of tissues that includes activation, recruitment, and proliferation of various immune cells and facilitates tissue regeneration and restoration of its normal functioning. The exact characteristics of a site of inflammation, such as composition of immune cells attracted to it and chemical factors secreted by these cells, are dependent on the nature of the damage that caused the inflammatory response. Acute inflammation usually resolves completely after the inflammation-causing lesion is repaired, but in certain cases, it may switch to a chronic inflammation, or in the case of systemic inflammation, which is not caused by infection or trauma, it might develop as a chronic form. A site of chronic inflammation can be viewed as “a wound that never heals” . Damage Transcription factors of the NF-κB family are one of the most important regulators of inflammation-associated gene expression. Each of these factors have the Rel homology domain, which is responsible for dimerization of NF-κB proteins and their binding to DNA . InactivPlant phenolic compounds might inhibit NF-κB activation at different stages of signal transduction . TreatmeThe inhibitory activity of curcumin towards NF-κB signaling pathway was also demonstrated. Treatment of MDA-MB-231 human breast cancer cell cultures with this phenolic compound inhibited NF-κB-mediated expression of CXCL-1 and -2 pro-inflammatory cytokines by preventing IκB phosphorylation . In RAW2Quercitin has activity towards NF-κB and its regulators. Treatment of Caco2 human colon adenocarcinoma cell culture with this phenolic compound downregulated expression of NF-κBp65, thus suppressing cellular motility and invasiveness . ExpressA certain degree of controversy exists regarding the modulatory activity of resveratrol towards the NF-κB signaling pathway. It was established that treatment of several human cervical cancer cell cultures with this phenolic compound resulted in reduction in the proliferation and induction of apoptosis; for CaSki cell cultures, these effects were the most prominent. In C33A, HeLa, CaLo, and CaSki cell cultures, the antiproliferative and proapoptotic activities of resveratrol were accompanied by a significant decrease in NF-κB p65 expression . In huma2O2 concentration caused by the upregulation of the expression of antioxidant enzymes, such as SOD1 and 2, accompanied by activation of NF-κB nuclear translocation and subsequent stimulation of the expression of pro-inflammatory proteins, such as TNF and CXC chemokines. These effects were observed for both cell cultures, but in HT-29 cell culture, they had no significant proapoptotic effect.Certain cases of genistein activity towards the NF-κB signaling pathway are also controversial. Genistein causes pro-apoptotic activity towards U266 human multiple myeloma cell culture by upregulating miR-29b that suppresses NF-κB p65 expression . It was 275, and pro-inflammatory cytokines [The anticancer and chemopreventive activity of plant polyphenols, carried out through activation of the NF-κB signaling pathway by these compounds, was demonstrated on a multitude of objects, including cell cultures, tumor xenografts, and the models of induced carcinogenesis. Suppression of NF-κB activation led to a decrease in the efficiency of antiapoptotic, pro-angiogenic, and prometastatic inflammatory signals in tumor tissue. Mechanisms of modulation of the NF-κB signaling pathway by plant polyphenols are summarized in ytokines . These pEscherichia coli [Campylobacter jejuni [F. nucleatum activate the β-catenin signaling pathway and suppress the antitumor activity of NK cells [H. pylori attenuate activity of tumor suppressors, stimulate proliferation, facilitate the acquisition of the mesenchymal phenotype, and modulate the host immune response [Human organisms are inhabited by microorganisms that modulate normal physiological processes  and varihia coli  and cytor jejuni  are the NK cells . CagA anresponse . Accumulresponse . Non-speresponse . It is aresponse , but it response .H. pylori culture growth by promoting changes in bacterial morphology and suppressing cell division [H. pylori-infected mice by inhibiting the adhesiveness and invasiveness of this microorganism [H. pylori culture in vitro, and alleviated H. pylori-induced gastritis in vivo by suppressing bacterial colonization of mucosa and abrogating inflammation elicited by the infection [Rubus crataegifolius and bark of Ulmus macrocarpa was described [H. pylori was determined by the ability of these substances to impair functioning of transmembrane energetic of this microorganism [Plant polyphenols have antibacterial properties , which adivision . Kaempfedivision . Similardivision . Antibacorganism . Antibacnfection . Similarescribed . The antorganism .C. jejuni as well. The antibacterial activity of curcumin was demonstrated by treatment of C. jejuni culture with this substance [C. jejuni-induced loosening of cellular junctions between intestinal epithelial cells and alleviates infection-induced apoptosis both in vitro and in vivo, thus facilitating epithelial barrier function and preventing development of inflammation [Natural phenolic compounds demonstrated antibacterial properties towards ubstance . Similarubstance . Treatmeammation ,303.F. nucleatum in vitro by disturbing integrity of the plasma membrane of this organism and by reducing its adhesiveness along with the ability of biofilm formation [F. nucleatum-induced inflammation [Enterobacteriaceae in the microflora of their progeny, accompanied by a lower risk of mammary cancer recurrence [EGCG, theaflavines and other tea polyphenols have antibacterial activity towards ormation . Similarammation . Treatmecurrence . The antBilophila wadsworthia in their microflora [−/− mice with curcumin in a similar tumorigenesis induction experiment resulted in a decrease in tumor burden and in prevention of cancer-associated changes in microbiota [Rubus occidentalis berries was able to reduce the number of tumors and abrogate inflammatory response during azoxymethane-induced carcinogenesis in mice, along with promotion of Neisseria and butyrate-producing bacteria growth and suppression of pathogenic H. pylori, Campylobacter, Bacteroides, and Prevotella [Sphingobacteriia, Bacilli and Gammaproteobacteria classes, Erysipelotrichales and Lactobacillales orders, and the Parabacteroides family, and by promoting an increase in the abundance of butyrate-producing Ruminococcaceae family [Firmicutes phylum in their microflora, while simultaneously decreasing abundance of Bacteroidetes [Escherichia and Enterococcus, while simultaneously increasing the abundance of butyrate-producing bacteria, such as Bytiricicoccus, Ruminococcus, and Clostridium. Induction of carcinogenesis with a high-fat diet in APCmin/+ mice was abrogated by neohesperidin by inducing the opposite direction of changes of abundance of Firmicutes and Bacteroidetes: this phenolic compound decreased the abundance of Bacteroidetes and increased the abundance of Firmicutes and Proteobacteria [Firmicutes and Bacteroidetes in these experiments might suggest that the analysis of cancer-associated microbiota changes at the phylum level may not be informative enough, as only a portion of species of aforementioned phyla are associated with carcinogenesis [Firmicutes phylum: this plant phenolic compound prevented the increase in the abundance of Anaerotruncus, Faecalibacterium and Streptococcus and decrease in the abundance of Clostridiaceae, Lactobacillis and Lachnospiraceae311 [Bacteroides and decrease in the abundance of Fusobacterium, Ruminococcus, and Veillonella. Dietary supplementation of mice xenograft with MCA-205 and E0771 murine cancer cells with castalagin-rich Myrciaria dubia berries led to sensibilization of MCA-205 to PD-1 inhibitor therapy, and circumvention of resistance of E0771 to these inhibitors [Alistipes, Blautia, and Ruminococcus.Microbiota-associated chemopreventive activity of plant polyphenols may be carried out not only by their antibacterial activity towards certain microorganisms, but also by modulation of species composition of gut microbiota. Dietary supplementation of sausages with powder of dried anthocyanine-rich berries reduced the number of intestinal tumors induced by azoxymethane treatment in rats, and alleviated the presence of pro-inflammatory croflora . Treatmecrobiota . Anthocyevotella . Treatmee family . Treatmeroidetes . This phbacteria . The oppogenesis . Resultsaceae311 . EGCG alhibitors . CastalaThese data emphasize the interplay between intestinal microbiota, the host organism immune system, and tumor microenvironment, and outline its crucial role in the process of tumorigenesis. Contacts with bacteria and their presence in the human organism since the earliest postnatal period are essential for priming the immune system for response to pathogen infections . The intPlant polyphenolic compounds can modulate tumor microenvironments either indirectly, by regulating the composition of intestinal microbiota, or directly, by mediating interactions between different types of immune cells. For example, polyphenols can stabilize the relative abundance of different immune cells on the intestinal mucosa and prevent development of chronic inflammation by preventing carcinogen-induced dysbiosis. Moreover, maintenance of intestinal eubiosis can be associated with sensitivity to immune checkpoint therapy; however, the exact molecular mechanisms responsible for this association are yet to be determined .Mechanisms of the modulation of tumor immune microenvironments by plant phenolic compounds are not limited to prevention of dysbiosis. During multiple in vitro experiments, an increase in the abundance of CD8+ T lymphocytes and enhancement of their cytotoxic activity upon polyphenol treatment were observed . Thus, tInteractions between immune cells in tumor microenvironments are targeted by the immune checkpoint inhibitors—anticancer drugs that prevent the suppression of cytotoxic T lymphocyte activity . These dWhen considering the antitumor and chemopreventive activity of plant polyphenols, another important aspect should be taken into account: natural phenolic compounds are not metabolically inert, and may undergo extensive chemical modification by host microbiota . It is eTreatment of MCF-7 human beast adenocarcinoma cell culture resulted in the suppression of the proliferation and induction of apoptosis by upregulating miR-10a-5p expression and subsequent inhibition of the PI3K/AKT signaling pathway . In HCT-The anticancer activity of urolithins was also demonstrated: treatment of Caco-2 colon cancer cell culture with these compounds resulted in suppression of the proliferation and induction of apoptosis , likely Data accumulated over the decades of study on the effect of natural polyphenols on human health suggest that these compounds exert antitumor and chemopreventive activities by multiple different mechanisms. Plant phenolic compounds can suppress metabolic activation of procarcinogens and reduce the levels of highly reactive compounds in the cell, thus preventing damage of genomic DNA. These substances demonstrate activity towards factors involved in epigenetic regulation, such as miRNAs and DNA- and histone-modifying enzymes, the misregulation of which probably contributes to malignant transformation. The ability of polyphenols to mitigate the pro-survival and growth-stimulatory effects of pro-inflammatory signals on tumor cells was also demonstrated. It was also established that phenolic compounds can modulate the composition of the intestinal microbiota throughout the entire process of tumorigenesis by suppressing growth of particular bacterial species and by changing the overall abundance of different taxa.At the same time, it was also established that the direction of the effect of a given natural phenolic compound on cellular metabolism depends on a multitude of factors, such as the exact chemical structure of a polyphenolic molecule and the type of cell culture or parameters of an animal model. In some cases, the effects of different plant polyphenols on a given physiological process were opposite: natural phenolic molecules might act either as AhR antagonists, thus suppressing expression of phase I xenobiotic metabolism enzymes, or as agonists of the same receptor. Under different conditions, polyphenols demonstrated both prooxidant and antioxidant activities. Increasing pro-inflammatory signaling by plant polyphenols was also described. The ambiguous nature of the influence of polyphenols on physiological processes involved in malignant transformation raises doubts about the possible anticancer and chemopreventive applications of these compounds. To rule out these doubts, an in-depth understanding of the mechanisms of interaction of phenolic substances with biological macromolecules and the physiological consequences of these interactions is required. One of the possible ways to achieve this degree of understanding is the application of high-throughput omics approaches to the study of polyphenol activity .High levels of chemical modifications of natural phenolic compounds by host microbiota, along with poor solubility of these compounds resulting in a low bioavailability, pose another challenge to their therapeutic application. This problem affects both purified polyphenols and polyphenol-rich foods and extracts. In some cases, even high doses of phenolic substances supplemented to individuals did not result in any significant presence of the substance in blood serum . To circDespite the long history of extensive study and the multifaceted antitumor and chemopreventve activity that encompass a vast number of physiological processes, it is still too early to introduce the polyphenol-based drugs into the clinical practice as tertiary chemopreventors. Yet, a polyphenol-rich diet could already be considered as an effective primary and secondary chemopreventive measure due to the multi-targeted blocking and suppressing activity exerted by the phenolic compounds it contains.


Nowadays, lung transplantation is a clinical reality for the treatment of benign end-stage respiratory diseases. Candidates’ selection and correct timing, evaluation and management of potential donors, therapy and post-transplant monitoring are certainly the most relevant aspects of this complicated path. Although great progress has been made in the overall approach, the results can still be improved, especially in terms of mortality and survival rates. The most relevant aspect is the incomplete understanding of the physiopathological mechanisms underlying the different phases of the donation–transplant process, from lung damage in the donor to chronic rejection in the recipient. A close interaction between basic and clinical research is mandatory, in order to have an increasingly positive impact on survival.We would like to introduce readers to some of the most relevant articles.Animal models are critical to aid in a better understanding of the complex molecular and cellular mechanisms of lung transplantation and improve clinical outcomes. The transplantation rat model, created more than 50 years ago by Asimacopoulos, is a complex procedure, both from the point of view of surgical technique and the management of the perioperative period . The intThe ex vivo lung perfusion (EVLP) system, first used in the clinical setting nearly 20 years ago, has demonstrated a high safety profile for screening lungs from a high-risk donor pool . CurrentDr Arni, in two papers, presents the results of two rat animal model studies, aimed at improving lung physiological and metabolic parameters. In a rat model of donation after circulatory death, it is reported that the use of a diazoxide mitochondrial-specific K (ATP) channel opener during EVLP can improve lung physiological and metabolic parameters, also reducing edema . AnotherTwo reviews by Dr Miceli and Niroomand provide an overview of experimental, preclinical and clinical studies supporting the application of EVLP as a therapeutic tool, focusing on cell therapies, cell product therapies and cytokine filtration ,10.Outcome after lung transplantation remains worse compared with other solid organ transplants, mainly due to the occurrence of primary graft dysfunction (PGD), which impacts both short-term and long-term survival. It is well established that there is a correlation between PGD-associated inflammation and the development of alloimmunity after lung transplantation, which promotes the onset of CLAD .The theme of PGD is assessed by an up-to-date review from the Leuven group; clinical, physiological, radiological and histological aspects are discussed, since a better understanding of acute lung failure after LTx can provide novel insights for future therapies .Early diagnosis of chronic organ dysfunction can impact survival by anticipating therapy, which is currently based on antifibrotic treatments and photopheresis.Dr Ram and colleagues assessed the correlations between parametric response mapping (PRM), a computed tomography methodology and biological markers, such as neutrophil and collagen I levels, in patients suffering from the two subtypes of chronic rejection, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS) . This Special Issue aims to address the current and more challenging topics in the lung transplant scenario, facilitating dynamic debate between clinicians and researchers and providing the necessary tools to merge the experiences.


Osteosarcoma (OS) is a primary malignant tumor of bone characterized by the formation of bone tissue or immature bone by tumor cells. Because of its multi-drug resistance, even with the improvement of chemotherapy and the use of targeted drugs, the survival rate of osteosarcoma (OS) is still less than 60%, and it is easy to metastasize, which is a difficulty for many clinicians and researchers. In recent years, with the continuous research on exosomes, it has been found that exosomes play a role in the diagnosis, treatment and chemotherapy resistance of osteosarcoma due to their unique properties. Exosomes can reduce the intracellular accumulation of chemotherapeutic drugs by mediating drug efflux, thus inducing chemotherapeutic resistance in OS cells. Exosomal goods  carried by exosomes also show great potential in affecting the drug resistance of OS. In addition, miRNA carried by exosomes and exosomes exist widely in tumor cells and can reflect the characteristics of parent cells, so it can also be used as a biomarker of OS. At the same time, the development of nanomedicine has given a new hope for the treatment of OS. Exosomes are regarded as good natural nano-carriers by researchers because of their excellent targeted transport capacity and low toxicity, which will play an important role in the field of OS therapy in the future. This paper reviews the internal relationship between exosomes and OS chemotherapy resistance, discusses the broad prospects of exosomes in the field of diagnosis and treatment of OS, and puts forward some suggestions for the study of the mechanism of OS chemotherapy resistance. Osteosarcoma (OS) is the most common primary malignant bone tumor originating from mesenchymal cell , 2. MostExtracellular vesicles (EVs) are small lipid-binding vesicles released by cells carrying heterogeneous items . This kind of goods can be transferred to other cells and can affect their physiological functions, thus playing an important role in cell-to-cell communication. EVs are divided into small EV (50-100 nm), medium EV (100-1000 nm) and large EV 1000-1500 nm) according to its size, and exosomes , micro vesicle (plasma membrane budding) and apoptotic body according to its origin/biogenesis  Figure. The pro00 nm accGarimella. et al. first reported the function of OS cell-derived exosomes, proposing that exosomes drive osteoclast bone resorption by disrupting the dynamic balance of bone reconstruction in the OS bone microenvironment (BME) . ExistinAccording to the former study, preoperative and postoperative chemotherapy regimens based on different combinations of doxorubicin, methotrexate, and cisplatin with the possible addition of ifosfamide, etoposide and, more recently, liposomal muramyl tripeptide phosphatidylethanolamine constitute the common treatment for primary conventional high-grade osteosarcoma (HGOS) –24. Howevia exosomes, leading to acquired drug resistance in drug-sensitive cells  –39. In 2in vitro chemoresistance to dox in dox-sensitive cells, and the expression of DANCER (encoding lncRNA) in exosomes of dox-resistant cells was higher than that in exosomes of dox-sensitive cells, testified the high expression of the lncRNA ANCR is related to dox-resistant in OS. Another study from the same year  has received a lot of attention from researchers because of its minimally invasive and reproducible nature –51. As wExisting studies confirm that transport from tumor cell exosomes can be observed in almost all types of liquid or solid tumors, and some of these studies found that exosomes with differential expression of miRNA and mRNA predict chemotherapy response in OS and can be used as biomarkers of tumor cells , 58. At In OS cells, exosomes can not only induce the transfer of drug resistance from drug-resistant cells to sensitive cells, promote tumor growth and development, but also inhibit tumor progression . Due to in vitro cellular assays, demonstrating that investigated miR-449a can inhibit osteosarcoma growth. However, because exogenous miRNA is easily degraded in the body, traditional miRNAs delivery methods do not usually achieve the expected effect  has not approved the use of exosomes as a clinical trial of OS therapy, on the one hand, because the mechanism and specific function of exosomes have not been fully understood, on the other hand, it is necessary to improve the production and storage of exosomes to avoid exosomes inactivation. Generally speaking, OS is still a puzzle to be developed, but the discovery of exosomes and the deepening of its research give us new hope. Therefore, despite many challenges, exosomes may play an important role in the diagnosis and treatment of OS as a biomarker for predicting and monitoring the therapeutic effect of OS, as a drug carrier or as a potential target for reversing drug resistance.CHF, YXW, PGX conceived the structure of the manuscript. CHF wrote the manuscript and drew the figures and was a major contributor in writing. JYW, XH, BJC revised the manuscript. All authors contributed to the article and approved the submitted version.


The development of regenerative medicine provides new options for the treatment of end-stage liver diseases. Stem cells, such as bone marrow mesenchymal stem cells, embryonic stem cells, and induced pluripotent stem cells (iPSCs), are effective tools for tissue repair in regenerative medicine. iPSCs are an appropriate source of hepatocytes for the treatment of liver disease due to their unlimited multiplication capacity, their coverage of the entire range of genetics required to simulate human disease, and their evasion of ethical implications. iPSCs have the ability to gradually produce hepatocyte-like cells (HLCs) with homologous phenotypes and physiological functions. However, how to induce iPSCs to differentiate into HLCs efficiently and accurately is still a hot topic. This review describes the existing approaches for inducing the differentiation of iPSCs into HLCs, as well as some challenges faced, and summarizes various parameters for determining the quality and functionality of HLCs. Furthermore, the application of iPSCs for in vitro hepatoprotective drug screening and modeling of liver disease is discussed. In conclusion, iPSCs will be a dependable source of cells for stem-cell therapy to treat end-stage liver disease and are anticipated to facilitate individualized treatment for liver disease in the future. Hepatopathy is a major cause of illness and death around the world, and it carries heavy medical and economic burdens . In ChinStem cells are promising tools of regenerative medicine to effectively treat a wide range of illnesses . MultiplIn the present review, we compare the development of the embryonic liver with the in vitro induction of human iPSCs into HLCs, and the importance of simulating the microenvironment during liver development is emphasized. Additionally, the conditions required for iPSC differentiation into hepatocytes and related phenotypes to be monitored are reviewed and summarized. Furthermore, recent developments in liver disease modeling and drug screening using iPSCs are discussed. The present review may provide a methodological reference for the efficient differentiation of iPSCs into hepatocytes and promote related medical applications.There are still many limitations to liver transplantation as the only effective treatment for end-stage liver disease; thus, there is an urgent need to discover new treatment options ,16,17. IAdditionally, animal models struggle to replicate the complexity of human diseases, while patient-derived iPSCs are genetically diverse, offering an opportunity to overcome related limitations . DiseaseHumans develop from a single totipotent cell, the zygote, which produces a blastocyst with an inner and outer cell mass during development . Among tAs an important hub for numerous physiological processes, the liver performs a variety of functions such as glycogen metabolism and storage, regulation of bile transport, detoxification, and albumin secretion . As mentBy simulating liver development in vitro, researchers have induced the generation of HLCs using iPSCs. How to produce HLCs with a primary hepatocyte phenotype and function is the key to the induction process, and various induction protocols are being developed with this aim ,36. SimiThe early stage. Although the induction protocols of the different experimental groups may vary in detail, they all generally go through three phases. Activin A and WNT3 signaling is used to promote definitive endoderm (DE) formation in the early stages of iPSC-induced differentiation into HLCs, and Activin/Nodal signaling can control the expression of the iPSC-specific gene NANOG and, thus, contribute to the maintenance of iPSC pluripotency ,45. WNT Other research groups have found that small-molecule compounds can also enhance the differentiation of iPSCs toward the endoderm. For instance, the addition of LY294002, a PI3K kinase inhibitor, inhibits phosphatidylinositol 3-kinase signaling , or CHIRThe intermediate stage. DE is induced during the liver specialization phase using BMP and FGF. These cytokines are released by the nearby cardiac mesoderm and septum transversum mesenchyme during the development of the liver, and promote liver differentiation by activating GATA4 and repressing genes involved in pancreatic development . ConsistThe final stage. Under various stimuli, liver progenitor cells have a bidirectional differentiation potential, producing bile duct cells or hepatocytes. HGF, oncostatin M (OSM), and the glucocorticoid dexamethasone (DEX) are necessary for differentiation. During the development of the liver, septal mesenchymal and endothelial cells release HGF, which binds to the tyrosine kinase receptor c-Met to improve cell survival and encourages hepatic progenitor cell proliferation . OSM is In other aspects of promoting hepatocyte production, nutrients may aid in the induction of hepatocyte maturation in addition to mimicking the liver milieu to encourage induced differentiation of hepatocytes. Extracellular amino acids (AAs), for instance, play a significant role in the metabolic maturation of hepatocytes. Adding AAs in excess of what is necessary for nutrition actively promotes hepatic metabolism and functional maturation in vitro and facilitates the expression of cytochrome P450 biotransformation enzymes. In controlling the hepatic transcriptional network, AAs perform a similar role to growth hormones in driving liver differentiation . To imprThe majority of earlier studies on the induction of iPSCs into hepatocytes involved iPSCs differentiating into final endodermal cells and then continuing induction into monolayer hepatocytes. However, because the process of liver development is controlled by the cooperative participation of many cells and tissues, these techniques have some limitations ,67,68,69The 3D culture system can produce a protein-based 3D scaffold that resembles the microenvironment of the human liver, allowing different types of liver cells to coexist and differentiate together and then receive various signaling molecules to eventually develop into hepatocytes in a coordinated manner . In 3D cIn contrast to conventional 2D culture techniques, Gieseck  and his Additionally, the 3D-HLC spheroids produced from the microporous culture platform also showed greater CYP3A4 enzyme activity and maintained high levels of hepatocyte nuclear factor (HNF4) expression. The sensitivity of 3D-HLC spheroids to toxic compounds in the liver was also improved in comparison to the 2D culture technique due to the higher numbers of drug-metabolizing enzymes . TherefoAlthough the aforementioned culture method demonstrated the benefits of the 3D system in the culture of HLCs, further study is required to produce fully functional mature hepatocytes. For instance, a number of experiments have been conducted to determine if coculturing with other liver cells enhances the development of hepatocytes ,77,78,79+ stellate cells in the retinol-treated group are two examples of results that coincide with hepatocyte-specific functions in vivo and show that the HLCs induced by the research team produced functional hepatocytes [In a recent study, iPSCs from a variety of healthy and steatohepatitis patients were used. They were cultured with retinoic acid (RA) for 4 days after being induced to form a well-defined endoderm. Next, hepatocytes were induced using hepatocyte maturation medium, and the result was the development of multicellular hepatocyte-like organs (HLOs) . Using iatocytes . This coOn the basis of the close association of multiple cells during liver development, Wu  and his A recent development in tissue engineering called 3D bioprinting makes it possible to precisely manufacture large parenchymal organ structures, which also provides new opportunities for liver regenerative medicine . ResearcIn summary, it appears that the induction process is difficult regardless of whether it uses 3D culture, conventional cytokines, or other small molecules that encourage the formation of hepatocytes. It is important to consider how to quickly and readily produce a high number of hepatocyte liver cells with liver function for clinical studies because these induction factors are very expensive, placing a significant financial burden on preclinical studies.For the effective production of functionally mature HLCs, the identification of the morphology, phenotype, and liver function of differentiation-generated HLCs is crucial. Despite the fact that numerous studies have been performed on the production of HLCs from iPSCs, there is no set test standard. We summarize the common tests that are currently used to evaluate the quality of HLCs. And regardless of the test, PHHs are the gold standard for testing because they are morphologically, phenotypically, and functionally highly comparable to healthy human liver cells ,93.In terms of morphology, HLCs should resemble primary hepatocytes in that they should be polygonal in shape and have a rising nucleus-to-cytoplasm ratio as differentiation progresses and the nucleus grows larger . MoreoveTo ascertain the differentiation effect of HLCs, the expression level of mRNA was primarily assessed by quantitative real-time PCR and compared with primary hepatocyte-specific genes. Among them, ALB, which is synthesized by mature hepatocytes, is frequently utilized as a reliable marker protein for liver function testing ,39. SeveiPSCs are used to study the pathological mechanisms in the development of diseases by virtue of their source diversity and gene specificity. Patient-specific disease models can be established, which not only provides a solution for personalized patient treatment but also holds promise for in vitro drug screening.The original organ or tissue is the best source of cells for in vitro disease modeling; nevertheless, primary cells from diseased tissues of patients are sometimes difficult to obtain and cannot maintain their original functional features when cultivated in vitro . iPSCs hIn previous studies, it was demonstrated that hepatocytes produced from iPSCs created utilizing a 2D differentiation strategy are efficient in the treatment of several liver disorders ,107,108.More recently, Ramli and colleagues  used a cRecently, liver diseases caused by urea cycle disorders  have been modeled with hiPSC-Heps, while in vitro modeling of ornithine transcarbamylase deficiency (OCTD), which is the most common cause of urea cycle disorders, has rarely been reported ,113,114.Furthermore, contrasting the differences in the pathological symptoms of liver disease models developed by patient- and healthy person-derived HLCs can help to personalize the disease treatment plan in the future. In this regard, a team of researchers developed iPSCs from liver-like tissues from Wolman disease patients, who show a significant build up of lipids in hepatocytes that can result in steatohepatitis or liver fibrosis in severe circumstances . The anaBuilding in vitro models of liver disease using human iPSC-induced HLCs has been successful, allowing researchers to better understand the disease’s pathophysiology and to develop new therapeutic treatment strategies . Three-dIn addition to disease modeling for the study of disease mechanisms, iPSC-based models can also be used for drug screening to discover new therapeutic approaches. iPSCs hold promise for in vitro drug testing by virtue of their source diversity and genetic specificity. Through the development of a liver organoid using iPSCs from Wolman patients, researchers have discovered possible therapeutic benefits of OCA and FGF19 in Wolman disease . LAL actIt is also important to note that adverse drug therapy reactions can result in major health issues that affect a number of bodily organs and cause disease or even death. One of these unfavorable effects is drug-induced liver injury (DILI), which accounts for more than 50% of cases of acute liver failure and is a common reason for the withdrawal of drugs from the market . MedicatHLCs produced using the current methodology nevertheless differ significantly from PHHs, posing substantial constraints for in vitro toxicity assessment. PHHs continue to be the gold standard for studies on liver disease . The levIn conclusion, obtaining HLCs with a functional maturity level that is more similar to that of primary hepatocytes is a continuing necessity for advancements in drug testing and in vitro screening. The potential of HLCs in drug testing is crucial to making it easier to explore drug treatment mechanisms, optimize compounds, and screen for drugs.Research to reprogram human somatic cells into iPSCs and direct their differentiation into HLCs offers hope for treating patients with liver failure. To enhance the maturation and functionality of hepatocyte-like cells, numerous new induction protocols based on conventional 2D induction systems have been proposed, such as coculture with other cell types ,119 and