DNA nanotechnology has produced a wide range of self-assembled structures, offering unmatched possibilities in terms of structural design. Because of their programmable assembly and precise control ...of size, shape, and function, DNA particles can be used for numerous biological applications, including imaging, sensing, and drug delivery. While the biocompatibility, programmability, and ease of synthesis of nucleic acids have rapidly made them attractive building blocks, many challenges remain to be addressed before using them in biological conditions. Enzymatic hydrolysis, low cellular uptake, immune cell recognition and degradation, and unclear biodistribution profiles are yet to be solved. Rigorous methodologies are needed to study, understand, and control the fate of self-assembled DNA structures in physiological conditions. In this review, we describe the current challenges faced by the field as well as recent successes, highlighting the potential to solve biology problems or develop smart drug delivery tools. We then propose an outlook to drive the translation of DNA constructs toward preclinical design. We particularly believe that a detailed understanding of the fate of DNA nanostructures within living organisms, achieved through thorough characterization, is the next required step to reach clinical maturity.
Fluorescent dye labeling of DNA oligonucleotides and nanostructures is one of the most used techniques to track their fate and cellular localization inside cells. Here, we report that intracellular ...fluorescence, and even FRET signals, cannot be correlated with the cellular uptake of intact DNA structures. Live cell imaging revealed high colocalization of cyanine-labeled DNA oligos and nanostructures with phosphorylated small-molecule cyanine dyes, one of the degradation products from these DNA compounds. Nuclease degradation of the strands outside and inside the cell results in a misleading intracellular fluorescent signal. The signal is saturated by the fluorescence of the degradation product (phosphorylated dye). To test our hypothesis, we synthesized a range of DNA structures, including Cy3- and Cy5-labeled DNA cubes and DNA tetrahedra, and oligonucleotides with different stabilities toward nucleases. All give fluorescence signals within the mitochondria after cellular uptake and strongly colocalize with a free phosphorylated dye control. Kinetics experiments revealed that uptake of stable DNA structures is delayed. We also studied several parameters influencing fluorescent data: stability of the DNA strand, fixation methods that can wash away the signal, position of the dye on the DNA strand, and design of FRET experiments. DNA nanostructures hold tremendous potential for biomedical applications and biotechnology because of their biocompatibility, programmability, and easy synthesis. However, few examples of successful DNA machines in vivo have been reported. We believe this contribution can be used as a guide to design better cellular uptake experiments when using fluorescent dyes, in order to further propel the biological development, and application of DNA nanostructures.
Over the past four decades, the field of structural DNA nanotechnology has evolved into an accessible approach to generating DNA nanostructures with precise control of size, geometry, and ...presentation of ligands. Moreover, the biocompatibility of DNA, its programmability, responsiveness to biological cues, ready synthesis, and ease of functionalization place DNA nanostructures as advantageous carriers for applications requiring the transport and selective release of cargo. However, as DNA nanostructures are translated to in vivo systems, they must be specifically designed to be compatible with biological environments. Some of these challenges include the optimization of their stability in biological media, their cellular uptake profile, and their drug encapsulation and release abilities. This review provides an overview of the field of structural DNA nanotechnology and outlines the progress toward the creation of DNA nanostructures to address challenges in biomedicine, as well as strategies that are currently adopted for interfacing them with living organisms.
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DNA nanostructures have emerged as promising building blocks in nanotechnology because of their programmable assembly and ready access to modifications, which enable their synthesis and assembly into virtually any architecture, a feature not yet achieved with most other materials. This vision has led to the development of three approaches to producing well-defined DNA nanostructures that take advantage of their full programmability. These advances in DNA nanotechnology, combined with the native biocompatibility of DNA, present an unparalleled opportunity to develop DNA nanostructures that are adapted for biomedical applications and display finely tuned cell uptake and delivery profiles. For instance, they have been examined as targeted therapies for improving the efficacy and reducing the side effects of current treatment approaches. This review outlines the recent progress on this topic as well as general strategies for adapting DNA nanostructures to address the challenges found at the interface with biology.
DNA nanostructures represent a promising platform for the development of well-defined carriers that can transport and selectively deliver cargo molecules to their prescribed location, enabling applications in drug delivery, bio-sensing, and bio-imaging. However, DNA nanostructures still need to be optimized to interface with biological environments. This review gives an overview of the field of structural DNA nanotechnology and outlines the recent progress in this direction, as well as strategies for adapting DNA nanostructures for in vivo applications.
The development of nucleic acid therapeutics has been hampered by issues associated with their stability and in vivo delivery. To address these challenges, we describe a new strategy to engineer DNA ...structures with strong binding affinity to human serum albumin (HSA). HSA is the most abundant protein in the blood and has a long circulation half-life (19 days). It has been shown to hinder phagocytosis, is retained in tumors, and aids in cellular penetration. Indeed, HSA has already been successfully used for the delivery of small-molecule drugs and nanoparticles. We show that conjugating dendritic alkyl chains to DNA creates amphiphiles that exhibit high-affinity (Kd in low nanomolar range) binding to HSA. Notably, complexation with HSA did not hinder the activity of silencing oligonucleotides inside cells, and the degradation of DNA strands in serum was significantly slowed. We also show that, in a site-specific manner, altering the number and orientation of the amphiphilic ligand on a self-assembled DNA nanocube can modulate the affinity of the DNA cage to HSA. Moreover, the serum half-life of the amphiphile bound to the cage and the protein was shown to reach up to 22 hours, whereas unconjugated single-stranded DNA was degraded within minutes. Therefore, adding protein-specific binding domains to DNA nanostructures can be used to rationally control the interface between synthetic nanostructures and biological systems. A major challenge with nanoparticles delivery is the quick formation of a protein corona (i.e., protein adsorbed on the nanoparticle surface) upon injection to biological media. We foresee such DNA cage–protein complexes as new tools to study the role of this protein adsorption layer with important implications in the efficient delivery of RNAi therapeutics in vitro and in vivo.
Few studies have examined sensory processing in mood disorders, including depression. The interactions between sensory inputs and adaptive behaviour have yet to be clarified in this pathology. We ...assessed sensory profiles among people with major depressive disorder (MDD) with the Adult/Adolescent Sensory Profile scale and determined whether sensory processing patterns were associated with clinical variables such as anxiety, depression, psychomotor retardation or self‐esteem. We compared 25 participants with MDD (MDD group) and 25 healthy controls (HC group) to identify sensory processing patterns (low registration, sensation seeking, sensory sensitivity and sensation avoiding). The Hamilton Depression Rating Scale and Clinical Outcomes in Routine Evaluation scale were used to assess depressive symptomatology. Both groups completed the Hamilton Anxiety Rating Scale, Frontal Assessment Battery and Rosenberg Self‐Esteem Inventory. The MDD group significantly differed from the HC group in each sensory processing patterns. They had higher low registration (p < 0.001), sensory sensitivity (p < 0.001) and sensation avoidance (p < 0.001) and lower sensation seeking (p = 0.005) than HC. Extreme sensory processing patterns in MDD patients were linked to depressive symptomatology, including anxiety. Sensory processing disorders should be assessed and taken into account when developing nondrug treatment strategies.
Repeated transcranial magnetic stimulation (rTMS) is a therapeutic brain-stimulation technique that is particularly used for drug-resistant depressive disorders. European recommendations mention the ...effectiveness of 30 to 64%. The failure rate of treatment is high and clinical improvement is visible only after a certain period of time. It would thus be useful to have indicators that could anticipate the success of treatment and more effectively guide therapeutic choices. We aimed to find predictive indicators of clinical improvement at 1 month after the start of rTMS treatment among the data collected during the care of patients with drug-resistant depression included in the Neuromodulation Unit of the Esquirol Hospital in Limoges since 2007. In total, 290 patients with a pharmaco-resistant depressive episode, according to the Hamilton Depression Rating Scale (HDRS) (score ≥8), before treatment who underwent a complete course of rTMS treatment and did not object to the use of their collected data were included. The clinical response in routine practice, corresponding to a decrease in the HDRS score of at least 50% from inclusion, was determined and complemented by interquartile analysis. A combination of factors predictive of clinical response during care, such as a short duration of the current depressive episode associated with a higher HDRS agitation item value (or a lower perceived sleepiness value) and a higher number of previous rTMS treatments, were identified as being useful in predicting the efficacy of rTMS treatment in routine clinical practice, thus facilitating the therapeutic choice for patients with drug-resistant depression.
Background Body image disorders are well documented in anorexia nervosa (AN); however, knowledge of interoceptive awareness (IA) in this population remains poor. This descriptive study investigated ...whether and how the representation of the interior of the body may have an impact on IA. Methods The representations and knowledge of the body interior were evaluated with a drawing task in 34 women with AN and 34 healthy controls (HCs). A lexicometric analysis was performed on the vocabulary used to describe the drawn body parts in a structured interview. It was assumed that the conceptual representation of the body interior could be affected by or influence IA. Thus, the relationship between IA, measured with the heartbeat task and the ischemia-induction test, and the drawings was explored. Other scales, such as those of body shape, awareness or satisfaction, were used to assess affective representations of the body. Results The drawing, lexicometric and IA results were similar in the two groups. No correlations were found among IA, body representation scores and representation level of body interior. Only the representation of bones by the AN group was significantly different. Discussion Increased visual attention to the skeleton or greater awareness of bone health could explain the stronger representation of bones in the AN group. The psychophysical therapy received by some AN participants (73%) did not seem to have influenced IA. Our results do not support a relationship between IA and the representation of the body interior. Clinical trial registration: https://clinicaltrials.gov/ , identifier NCT03988218.
The neurotrophin receptors are known to promote growth and proliferation of glioblastoma cells. Their functions in spreading glioblastoma cell aggressiveness to the microenvironment through exosome ...release from glioblastoma cells are unknown. Considering previous reports demonstrating that YKL-40 expression is associated with undifferentiated glioblastoma cancer stem cells, we used YKL-40-silenced cells to modulate the U87-MG differentiated state and their biological aggressiveness. Herein, we demonstrated a relationship between neurotrophin-receptors and YKL-40 expression in undifferentiated cells. Differential functions of cells and derived-exosomes were evidenced according to neurotrophin receptor content and differentiated cell state by comparison with control pLKO cells. YKL-40 silencing of glioblastoma cells impairs proliferation, neurosphere formation, and their ability to induce endothelial cell (HBMEC) migration. The modulation of differentiated cell state in YKL-40-silenced cells induces a decrease of TrkB, sortilin and p75NTR cellular expressions, associated with a low-aggressiveness phenotype. Interestingly, TrkB expressed in exosomes derived from control cells was undetectable in exosomes from YKL-40 -silenced cells. The transfer of TrkB-containing exosomes in YKL-40-silenced cells contributed to restore cell proliferation and promote endothelial cell activation. Interestingly, in U87 MG xenografted mice, TrkB-depleted exosomes from YKL-40-silenced cells inhibited tumor growth in vivo. These data highlight that TrkB-containing exosomes play a key role in the control of glioblastoma progression and aggressiveness. Furthermore, TrkB expression was detected in exosomes isolated from plasma of glioblastoma patients, suggesting that this receptor may be considered as a new biomarker for glioblastoma diagnosis.
RNA-based therapeutics are emerging as a powerful platform for the treatment of multiple diseases. Currently, the two main categories of nucleic acid therapeutics, antisense oligonucleotides and ...small interfering RNAs (siRNAs), achieve their therapeutic effect through either gene silencing, splicing modulation or microRNA binding, giving rise to versatile options to target pathogenic gene expression patterns. Moreover, ongoing research seeks to expand the scope of RNA-based drugs to include more complex nucleic acid templates, such as messenger RNA, as exemplified by the first approved mRNA-based vaccine in 2020. The increasing number of approved sequences and ongoing clinical trials has attracted considerable interest in the chemical development of oligonucleotides and nucleic acids as drugs, especially since the FDA approval of the first siRNA drug in 2018. As a result, a variety of innovative approaches is emerging, highlighting the potential of RNA as one of the most prominent therapeutic tools in the drug design and development pipeline. This review seeks to provide a comprehensive summary of current efforts in academia and industry aimed at fully realizing the potential of RNA-based therapeutics. Towards this, we introduce established and emerging RNA-based technologies, with a focus on their potential as biosensors and therapeutics. We then describe their mechanisms of action and their application in different disease contexts, along with the strengths and limitations of each strategy. Since the nucleic acid toolbox is rapidly expanding, we also introduce RNA minimal architectures, RNA/protein cleavers and viral RNA as promising modalities for new therapeutics and discuss future directions for the field.
Abstract Introduction Access to data concerning mental health, particularly alcohol use disorders (AUD), in sub-Saharan Africa is very limited. This study aimed to estimate AUD prevalence and ...identify the associated factors in Togo and Benin. Methods A cross-sectional study was conducted between April and May 2022, targeting individuals aged 18 years and above in the Yoto commune of Togo and the Lalo commune of Benin. Subjects were recruited using a multi-stage random sampling technique. AUD diagnoses were made using the MINI adapted to DSM-5 criteria. Our study collected sociodemographic information, data on psychiatric comorbidities, stigmatization, and assessed cravings, using a series of scales. The association between AUD and various factors was analyzed using multivariable logistic regression. Results In Togo, 55 of the 445 people investigated had AUD (12.4%; 95% CI: 9.5-15.7%). Among them, 39 (70.9%) had severe AUD and the main associated comorbidities were suicidal risk (36.4%), and major depressive disorder (16.4%). Associated factors with AUD were male gender (aOR: 11.3; 95% CI: 4.8–26.7), a higher Hamilton Depression Rating Scale (HDRS) score (aOR: 1.2; 95% CI: 1.1–1.3) and a lower Stigma score measured by the Explanatory Model Interview Catalogue (EMIC) (aOR: 0.9; 95% CI: 0.8–0.9). The stigma scores reflect perceived societal stigma towards individuals with AUD. In Benin, 38 of the 435 people investigated had AUD (8.7%; 95% CI: 6.4–11.7), and the main associated comorbidities were suicidal risk (18.4%), tobacco use disorder (13.2%) and major depressive episode (16.4%). Associated factors with AUD were male gender (aOR: 6.4; 95% CI: 2.4–17.0), major depressive disorder (aOR: 21.0; 95% CI: 1.5-289.8), suicidal risk (aOR: 3.7; 95% CI: 1.2–11.3), a lower Frontal Assessment Battery (FAB) score (aOR:0.8; 95% CI: 0.8–0.9) and a lower perceived stigma score (by EMIC )(aOR: 0.9; 95% CI: 0.8–0.9). Conclusion In these communes of Togo and Benin, AUD prevalence is notably high. A deeper understanding of the disease and its local determinants, paired with effective prevention campaigns, could mitigate its impact on both countries.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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