Paclitaxel (PTX) is among the most commonly used first-line drugs for cancer chemotherapy. However, its poor water solubility and indiscriminate distribution in normal tissues remain clinical ...challenges. Here we design and synthesize a highly water-soluble nucleolin aptamer-paclitaxel conjugate (NucA-PTX) that selectively delivers PTX to the tumor site. By connecting a tumor-targeting nucleolin aptamer (NucA) to the active hydroxyl group at 2' position of PTX via a cathepsin B sensitive dipeptide bond, NucA-PTX remains stable and inactive in the circulation. NucA facilitates the uptake of the conjugated PTX specifically in tumor cells. Once inside cells, the dipeptide bond linker of NucA-PTX is cleaved by cathepsin B and then the conjugated PTX is released for action. The NucA modification assists the selective accumulation of the conjugated PTX in ovarian tumor tissue rather than normal tissues, and subsequently resulting in notably improved antitumor activity and reduced toxicity.
Intricately interwoven topologies are continually being synthesized and are ultimately equally versatile and significant at the nanoscale level; however, reports concerning ravel structures, which ...are highly entwined new topological species, are extremely rare and fraught with tremendous synthesis challenges. To solve the synthesis problem, a tetrapodontic pyridine ligand L1 with two types of olefinic bond units and two Cp*M‐based building blocks (E1, M=Rh; E2, M=Ir) featuring large conjugated planes was prepared to perform the self‐assembly. Two unprecedented 5+10 icosanuclear molecular 4‐ravels containing four crossings were obtained by parallel‐displaced π⋅⋅⋅π interactions in a single‐step strategy. Remarkably, reversible structural transformations between the 4‐ravel and the corresponding metallocage could be realized by concentration changes and solvent‐ and guest‐induced effects. X‐ray crystallographic data and NMR spectroscopy provide full confirmation of these phenomena.
Two unprecedented 5+10 icosanuclear molecular 4‐ravels containing four crossings have been generated using a single‐step strategy. This topology is achieved by utilizing parallel‐displaced π⋅⋅⋅π interactions with carefully selected naphthoquinoyl Cp*M building blocks and X‐shaped pyridyl ligands.
Cardiovascular and metabolic disease (CMD) remains a main cause of premature death worldwide. Berberine (BBR), a lipid-lowering botanic compound with diversified potency against metabolic disorders, ...is a promising candidate for ameliorating CMD. The liver is the target of BBR so that liver-site accumulation could be important for fulfilling its therapeutic effect. In this study a rational designed micelle (CTA-Mic) consisting of α-tocopheryl hydrophobic core and on-site detachable polyethylene glycol-thiol shell is developed for effective liver deposition of BBR. The bio-distribution analysis proves that the accumulation of BBR in liver is increased by 248.8% assisted by micelles. Up-regulation of a range of energy-related genes is detectable in the HepG2 cells and in vivo. In the high fat diet-fed mice, BBR-CTA-Mic intervention remarkably improves metabolic profiles and reduces the formation of aortic arch plaque. Our results provide proof-of-concept for a liver-targeting strategy to ameliorate CMD using natural medicines facilitated by Nano-technology.
Diabetic neuropathic pain (DNP) is a common and distressing complication in patients with diabetes, and the underlying mechanism remains unclear. Tricyclic antidepressants (TCAs) and serotonin and ...norepinephrine reuptake inhibitors (SNRIs) are recommended as first-line drugs for DNP. Ammoxetine is a novel and potent SNRI that exhibited a strong analgesic effect on models of neuropathic pain, fibromyalgia-related pain, and inflammatory pain in our primary study. The present study was undertaken to investigate the chronic treatment properties of ammoxetine on DNP and the underlying mechanisms for its effects.
The rat model of DNP was established by a single streptozocin (STZ) injection (60 mg/kg). Two weeks after STZ injection, the DNP rats were treated with ammoxetine (2.5, 5, and 10 mg/kg/day) for 4 weeks. The mechanical allodynia and locomotor activity were assayed to evaluate the therapeutic effect of ammoxetine. In mechanism study, the activation of microglia, astrocytes, the protein levels of pro-inflammatory cytokines, the mitogen-activated protein kinases (MAPK), and NF-κB were evaluated. Also, microglia culture was used to assess the direct effects of ammoxetine on microglial activation and the signal transduction mechanism.
Treatment with ammoxetine for 4 weeks significantly relieved the mechanical allodynia and ameliorated depressive-like behavior in DNP rats. In addition, DNP rats displayed increased activation of microglia in the spinal cord, but not astrocytes. Ammoxetine reduced the microglial activation, accumulation of pro-inflammatory cytokines, and activation of p38 and c-Jun N-terminal kinase (JNK) in the spinal cord of DNP rats. Furthermore, ammoxetine displayed anti-inflammatory effects upon challenge with LPS in BV-2 microglia cells.
Our results suggest that ammoxetine may be an effective treatment for relieving DNP symptoms. Moreover, a reduction in microglial activation and pro-inflammatory release by inhibiting the p-p38 and p-JNK pathways is involved in the mechanism.
Conspectus Currently, flexible and stretchable biomimetic sensing electronics have obtained a great deal of attention in various areas, such as human–machine interfaces, robotic smart skins, health ...care monitoring, and biointegrated devices. In contrast with the traditional rigid and fragile silicon-based electronics, flexible and stretchable sensing electronics can efficiently capture high-quality signals when integrated on curved surfaces due to their elastic and conformal characters, which are expected to play many important roles in the foreseeable age of intelligence. Its realization strongly relies on rapid advances in the development of high-performance and versatile flexible and stretchable sensors, and effective ways to achieve high performance are rational designs of the sensing materials and microstructural configurations. This Account showcases the recent progress in flexible and stretchable biomimetic sensors covering several critical aspects of materials, structures, and applications. Nature-inspired active matter and architectures, which have been well-tuned by evolution through millions of years of optimization, provide us the best learning choices to overcome the restrictions of current sensor techniques such as low sensitivity, instability, and delayed response time. Biomimetic sensing materials and microstructural patterns can efficiently acquire synthetic response abilities, endowing the new-type flexible sensors considered as “smart” electronic components on account of the counterparts to living organisms. Moreover, the developments of diverse functions and multifunctional applications become more and more important in the creation of novel flexible electronics beyond those existing technologies. For instance, flexible and stretchable sensors with the capability of mimicking various human behavioral patterns can be developed to boost the emergence of artificial robots, which can take the place of human beings in strenuous activities, enabling progress in social science, technology, and productivity to improve the quality of human life. For the above purpose, inspired by the in-depth understanding of working principles of living organisms how to operate their natural characteristics, sensing materials with stimuli response (light, humidity, mechanics, etc.) and multifunctionalities (superhydrophobicity, degradation, self-healing, etc.) provide distinctive and multiple detection features generally encountered in their traditional counterparts. In addition, artificial micro- to nanostructures derived from naturally existing high sensitivity structures (such as insect crack or leaves) and stretchable configurations (wrinkle, texture, mesostructures, etc.) offer additional feasible strategies for producing favorable sensitivity and stretchability. Flexible and stretchable biomimetic sensors with analogous senses to those of human beings (such as tactile and auditory senses) have attracted tremendous attention for their diverse applications for next generation smart electronics. The long-term progress of these novel sensors influencing the next generations of bioinspired intelligence systems and medical electronics are also envisioned.
Superhydrophobic surfaces have shown versatile applications in waterproofing, self‐cleaning, drag reduction, selective absorption, etc. The most convenient and universally applicable approach to ...forming superhydrophobic surfaces is by coating; however, currently, superhydrophobic, smart coatings with flexibility and multiple functions for wearable sensing electronics are not yet reported. Here, a highly flexible multifunctional smart coating is fabricated by spray‐coating multiwalled carbon nanotubes dispersed in a thermoplastic elastomer solution, followed by treatment with ethanol. The coatings not only endow various substrate materials with superhydrophobic surfaces, but can also respond to stretching, bending, and torsion—a property useful for flexible sensor applications. The coatings show superior sensitivity (gauge factor of 5.4–80), high resolution (1° of bending), a fast response time (<8 ms), a stable response over 5000 stretching–relaxing cycles, and wide sensing ranges (stretching: over 76%, bending: 0°–140°, torsion: 0–350 rad m−1). Moreover, multifunctional coatings with thicknesses of only 1 µm can be directly applied to clothing for full‐range and real‐time detection of human motions, which also show extreme repellency to water, acid, and alkali, which helps the sensors to work under wet and corrosive conditions.
A multifunctional, stretchable smart coating is fabricated by spray‐coating multiwalled carbon nanotubes dispersed in a thermoplastic elastomer solution, followed by treatment with ethanol. The coatings are superhydrophobic and piezoresistive, for water repellency and wearable strain‐sensor applications. The extreme repellency to water, UV, acid, and alkali characteristics of the coating endow highly sensitive and stable sensing performance under wet/corrosive conditions.
Aptamers are oligonucleotide sequences with a length of about 25–80 bases which have abilities to bind to specific target molecules that rival those of monoclonal antibodies. They are attracting ...great attention in diverse clinical translations on account of their various advantages, including prolonged storage life, little batch-to-batch differences, very low immunogenicity, and feasibility of chemical modifications for enhancing stability, prolonging the half-life in serum, and targeted delivery. In this Review, we demonstrate the emerging aptamer discovery technologies in developing advanced techniques for producing aptamers with high performance consistently and efficiently as well as requiring less cost and resources but offering a great chance of success. Further, the diverse modifications of aptamers for therapeutic applications including therapeutic agents, aptamer–drug conjugates, and targeted delivery materials are comprehensively summarized.
Summary
Akkermansia muciniphila (A. muciniphila), an intestinal symbiont colonizing in the mucosal layer, is considered to be a promising candidate as probiotics. A. muciniphila is known to have an ...important value in improving the host metabolic functions and immune responses. Moreover, A. muciniphila may have a value in modifying cancer treatment. However, most of the current researches focus on the correlation between A. muciniphila and diseases, and little is known about the causal relationship between them. Few intervention studies on A. muciniphila are limited to animal experiments, and limited studies have explored its safety and efficacy in humans. Therefore, a critical analysis of the current knowledge in A. muciniphila will play an important foundation for it to be defined as a new beneficial microbe. This article will review the bacteriological characteristics and safety of A. muciniphila, as well as its causal relationship with metabolic disorders, immune diseases and cancer therapy.
Akkermansia muciniphila (A. muciniphila), an intestinal symbiont colonizing in the mucosal layer, is considered to be a promising candidate as a probiotics. Most of the current researches focus on the correlation between A. muciniphila and diseases, and little is known about the causal relationship between them. This article will review the bacteriological characteristics and safety of A. muciniphila, as well as its causal relationship with metabolic disorders, immune diseases, and cancer therapy.
Abstract
Sclerostin negatively regulates bone formation by antagonizing Wnt signalling. An antibody targeting sclerostin for the treatment of postmenopausal osteoporosis was approved by the U.S. Food ...and Drug Administration, with a boxed warning for cardiovascular risk. Here we demonstrate that sclerostin participates in protecting cardiovascular system and inhibiting bone formation via different loops. Loop3 deficiency by genetic truncation could maintain sclerostin’s protective effect on the cardiovascular system while attenuating its inhibitory effect on bone formation. We identify an aptamer, named aptscl56, which specifically targets sclerostin loop3 and use a modified aptscl56 version, called Apc001PE, as specific in vivo pharmacologic tool to validate the above effect of loop3. Apc001PE has no effect on aortic aneurysm and atherosclerotic development in
ApoE
−/−
mice and
hSOST
ki
.ApoE
−/−
mice with angiotensin II infusion. Apc001PE can promote bone formation in
hSOST
ki
mice and ovariectomy-induced osteoporotic rats. In summary, sclerostin loop3 cannot participate in protecting the cardiovascular system, but participates in inhibiting bone formation.
Although the selective synthesis of complicated supramolecular architectures has seen significant progress in recent years, the exploration of the properties of these complexes remains a fascinating ...challenge. Herein, a series of new supramolecular topologies, metalla2catenanes and Borromean ring assemblies, were constructed based on appropriate Cp*Rh building blocks and two rigid alkynyl pyridine ligands (
L1
,
L2
)
via
coordination-driven self-assembly. Interestingly, minor differences between the two rigid alkynyl pyridine ligands with/without organic substituents led to products with dramatically different topologies. Careful structural analysis showed that π-π stacking interactions play a crucial role in stabilizing these 2catenanes and Borromean ring assemblies, while also promoting nonradiative transitions and triggering photothermal conversion in both the solution and the solid states. These results were showcased through comparative studies of the NIR photothermal conversion efficiencies of the Borromean ring assemblies, 2catenanes and metallarectangles, which exhibited a wide range of photothermal conversion efficiencies (12.64-72.21%). The influence of the different Cp*Rh building blocks on the NIR photothermal conversion efficiencies of their assemblies was investigated. Good photothermal conversion properties of the assemblies were also found in the solid state. This study provides a new strategy to construct valuable half-sandwich-based NIR photothermal conversion materials while also providing promising candidates for the further development of materials science.
The selective synthesis of three kinds of supermolecular topologies, molecular Borromean ring, 2catenane and metallarectangle based on two alkynyl ligands is presented. Remarkably, the NIR photothermal conversion efficiency was found to improve as the π-π stacking increases.
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