Conspectus Plants in the Schisandraceae family are important components of the traditional Chinese herbal medicines and are often used to treat various illnesses. Therefore, these Schisandraceae ...plants are valuable sources for the discovery of new chemical entities for novel therapeutic development. Considerable progress has been made in the identification of bioactive and structurally novel triterpenoids from the Schisandraceae family in the past two decades. In particular, Sun and co-workers have successfully isolated over 100 nortriterpenoids from the Schisandraceae family. Some of these nortriterpenoids have strong inhibitory activities toward hepatitis, tumors, and HIV-1. However, the natural scarcity of these nortriterpenoids in the Schisandraceae plants has hampered their isolation and further biomedical development, and their biosynthesis has not been fully elucidated. It is therefore important and urgent to develop efficient and streamlined total syntheses of these medicinally important nortriterpenoids. Such syntheses will provide sufficient materials for detailed biological studies as well as new synthetic analogues and probe molecules to improve their biological functions and elucidate their mode of actions. However, because of their structural novelty and complexity, the total syntheses of these nortriterpenoid natural products present a significant challenge for synthetic chemists, despite the progress made in organic synthesis, particularly total synthesis, in the 20th century and since the beginning of the 21st century. New synthetic methodologies and strategies therefore need to be invented and developed to facilitate the total syntheses of these nortriterpenoid natural products. With this in mind, our group has spent the last 15 years, ever since the isolation of micrandilactone A (1) by Sun and co-workers in 2003 (Sun et al. Org. Lett. 2003, 5, 1023−1026 ), working on synthetic studies with a view to developing methods and strategies for the total syntheses of schinortriterpenoids. Enabling methods such as a thiourea/Pd-catalyzed alkocycarbonylative annulation and a thiourea/Co-catalyzed Pauson–Khand reaction have been developed under these circumstances to form the key ring systems and stereocenters of these complex target molecules. These methodological advances have led us to the first total syntheses of schindilactone A (2), lancifodilactone G acetate (6a), 19-dehydroxyarisandilactone A (9), and propindilactone G (10) with diverse structural features via a branching-oriented strategy. The chemistry developed during our total synthesis campaign has not only helped us to deal with various challenges encountered in the syntheses of the four target molecules, but has also opened up new avenues for synthesizing other naturally occurring schinortriterpenoids and their derivatives, which will likely result in molecules with improved biological functions and tool compounds to enable elucidation of their mechanism of actions or potential cellular targets. This Account highlights the chemistry evolution of our schinortriterpenoid syntheses.
Conspectus Precision medicine requires noninvasive and accurate early diagnosis and individually appropriate treatments. Phototheranostics has been considered a frontier precision medical technology ...to provide rapid and safe disease localization and efficient cure. Harnessing the power of advanced nanomedicine with photonics, phototheranostics is rapidly developing and progressively becoming irreplaceable in modern medicine. Nanoscale semiconducting materials, such as inorganic semiconductors, organic conjugated polymers, and small molecules with photonic properties, have been extensively explored in medical imaging (fluorescence imaging, optical coherence tomography, and photoacoustic PA imaging) and phototherapy (photothermal, photodynamic, and photocontrolled combination therapies). In practical clinical applications, organic semiconducting materials, because of their biocompatibility and natural metabolism, are preferred over inorganic materials for phototheranostics. Supramolecular self-assembly is considered a significant method for preparing organic detachable and multifunctional phototheranostics, as supramolecular interactions, such as π–π interactions, hydrogen bonding, hydrophobic effects, and electrostatic interactions, are non-covalent and dynamic. Developing new and effective organic supramolecular phototheranostics requires exploration of well-designed basic building blocks with optical properties, understanding of the assembly at the nanoscale, and optimization of the phototheranostics with unique and distinctive multifunctional efficacy. In this Account, we summarize our recent work on the development of small molecular semiconducting perylene diimide (SPDI) for advanced phototheranostics. SPDI is modified to have strong near-infrared absorption beyond 700 nm by the push–pull electronic effect and owns the merits of remarkable photostability, large extinction coefficient, and high photothermal conversion efficiency. By hydrophilic modification, the amphiphile can self-assemble into a nanomicellar structure that allows PA imaging and can serve as a photothermal conversion agent. After theranostics delivery is achieved, this SPDI can be further functionalized for multimodality imaging and photothermally triggered multimodal synergistic therapy. Several well-designed asymmetric structures of SPDI can be obtained by stepwise modification of imides. It is noteworthy that the self-assembly of SPDI is controllable, allowing the preparation of different-sized spherical nanoparticles and rodlike nanoparticles and nanodroplets. For biomedical applications of SPDI phototheranostics (SPDIPTs), the size effect of SPDIPTs has been highlighted in lymph node mapping and cancer imaging. The PA properties and targeting peptide modification of SPDIPTs have brought about the ultrasensitive imaging of early thrombus. The supramolecular nanoconstructs of SPDIPTs further permit multimodality-imaging-guided cancer therapy. In brief, the design of SPDIPTs considers synthetic chemistry, supramolecular self-assembly, nanotechnology, and photonics. Furthermore, SPDIPTs have diverse biomedical applications and offer many opportunities for advancing nanomedicine.
Targeted cancer therapy aims to achieve specific elimination of cancerous but not normal cells. Recently, PIWI proteins, a subfamily of the PAZ-PIWI domain (PPD) protein family, have emerged as ...promising candidates for targeted cancer therapy. PPD proteins are essential for small noncoding RNA pathways. The Argonaute subfamily partners with microRNA and small interfering RNA, whereas the PIWI subfamily partners with PIWI-interacting RNA (piRNA). Both PIWI proteins and piRNA are mostly expressed in the germline and best known for their function in transposon silencing, with no detectable function in mammalian somatic tissues. However, PIWI proteins become aberrantly expressed in multiple types of somatic cancers, thus gaining interest in targeted therapy. Despite this, little is known about the regulatory mechanism of PIWI proteins in cancer. Here we report that one of the four PIWI proteins in humans, PIWIL1, is highly expressed in gastric cancer tissues and cell lines. Knocking out the PIWIL1 gene (PIWIL1-KO) drastically reduces gastric cancer cell proliferation, migration, metastasis, and tumorigenesis. RNA deep sequencing of gastric cancer cell line SNU-1 reveals that KO significantly changes the transcriptome, causing the up-regulation ofmost of its associated transcripts. Surprisingly, few bona fide piRNAs exist in gastric cancer cells. Furthermore, abolishing the piRNA-binding activity of PIWIL1 does not affect its oncogenic function. Thus, PIWIL1 function in gastric cancer cells is independent of piRNA. This piRNA-independent regulation involves interaction with the UPF1-mediated nonsense-mediated mRNA decay (NMD) mechanism. Altogether, our findings reveal a piRNA-independent function of PIWIL1 in promoting gastric cancer.
Considering that the human brain uses ≈1015 synapses to operate, the development of effective artificial synapses is essential to build brain‐inspired computing systems. In biological synapses, the ...voltage‐gated ion channels are very important for regulating the action‐potential firing. Here, an electrolyte‐gated transistor using WO3 with a unique tunnel structure, which can emulate the ionic modulation process of biological synapses, is proposed. The transistor successfully realizes synaptic functions of both short‐term and long‐term plasticity. Short‐term plasticity is mimicked with the help of electrolyte ion dynamics under low electrical bias, whereas the long‐term plasticity is realized using proton insertion in WO3 under high electrical bias. This is a new working approach to control the transition from short‐term memory to long‐term memory using different gate voltage amplitude for artificial synapses. Other essential synaptic behaviors, such as paired pulse facilitation, the depression and potentiation of synaptic weight, as well as spike‐timing‐dependent plasticity are also implemented in this artificial synapse. These results provide a new recipe for designing synaptic electrolyte‐gated transistors through the electrostatic and electrochemical effects.
An electrolyte‐gated transistor using WO3 with a unique tunnel structure to successfully emulate the synaptic functions of both short‐term and long‐term plasticity is proposed. Short‐term plasticity is mimicked with the help of electrolyte ion dynamics under low gate bias, and the long‐term plasticity is realized via proton insertion in WO3 under high gate bias.
By modeling the uncertainty of spinning reserves provided by energy storage with probabilistic constraints, a new optimal scheduling mode is proposed in this paper for minimizing the operating costs ...of an isolated microgrid (MG) by using chance-constrained programming. The model is transformed into a readily solvable mixed integer linear programming formulation in general algebraic modeling system (GAMS) via a proposed discretized step transformation approach and finally solved by applying the CPLEX solver. By properly setting the confidence levels of the spinning reserve probability constraints, the MG operation can achieve a tradeoff between reliability and economy. The test results on the modified Oak Ridge National Laboratory Distributed Energy Control and Communication lab MG test system reveal that the proposal significantly exceeds the commonly used hybrid intelligent algorithm with much better and more stable optimization results and significantly reduced calculation times.
A series of easily prepared Lewis basic ionic liquids were developed for cyclic carbonate synthesis from epoxide and carbon dioxide at low pressure without utilization of any organic solvents or ...additives. Notably, quantitative yields together with excellent selectivity were attained when 1,8‐diazabicyclo5.4.0undec‐7‐enium chloride (HDBUCl) was used as a catalyst. Furthermore, the catalyst could be recycled over five times without appreciable loss of catalytic activity. The effects of the catalyst structure and various reaction parameters on the catalytic performance were investigated in detail. This protocol was found to be applicable to a variety of epoxides producing the corresponding cyclic carbonates in high yields and selectivity. Therefore, this solvent‐free process thus represents an environmentally friendly example for the catalytic conversion of carbon dioxide into value‐added chemicals by employing Lewis basic ionic liquids as catalyst. A possible catalytic cycle for the hydrogen bond‐assisted ring‐opening of epoxide and activation of carbon dioxide induced by the nucleophilic tertiary nitrogen of the ionic liquid was also proposed.
Ionic liquids (ILs), a kind of novel green medium composed entirely of cations and anions, have attracted considerable attention due to their unique properties such as non-volatility, tunable ...polarity, high stability and so on. In this article, the latest progress on the absorption and subsequent conversion of CO2 by using ILs as absorbents, catalysts or promoters will be summarized. The chemical absorption performance of ILs, especially task-specific ionic liquids (TSILs) such as amino-functionalized ILs, superbase-derived protic ILs has been systematically illustrated. Although significant advances have been made, extensive energy input in the desorption process to recover absorbents would still be a crucial barrier to realizing practical carbon capture and sequestration (CCS). On the other hand, efficient applications of CO2 in the synthesis of valuable compounds such as organic carbonates, urea derivatives, oxazolidinones and formic acid can also be promoted by employing TSILs as catalysts/reaction media. We anticipate that an integration of chemical capture of CO2 with its utilization, a so-called CO2 capture and utilization (CCU) protocol would be an ideal strategy to solve the energy penalty problem in common CCS without the need for additional heat desorption. The essence of this CCU concept is to use TSILs for CO2 capture and substantial activation, which could allow catalytic transformation of CO2 to be accomplished smoothly under low pressure (ideally at 1 atm).
Delayed or impaired wound healing is a major health issue worldwide, especially in patients with diabetes and atherosclerosis. Here we show that expression of the circular RNA circ-Amotl1 accelerated ...healing process in a mouse excisional wound model. Further studies showed that ectopic circ-Amotl1 increased protein levels of Stat3 and Dnmt3a. The increased Dnmt3a then methylated the promoter of microRNA miR-17, decreasing miR-17-5p levels but increasing fibronectin expression. We found that Stat3, similar to Dnmt3a and fibronectin, was a target of miR-17-5p. Decreased miR-17-5p levels would increase expression of fibronectin, Dnmt3a, and Stat3. All of these led to increased cell adhesion, migration, proliferation, survival, and wound repair. Furthermore, we found that circ-Amotl1 not only increased Stat3 expression but also facilitated Stat3 nuclear translocation. Thus, the ectopic expressed circ-Amotl1 and Stat3 were mainly translocated to nucleus. In the presence of circ-Amotl1, Stat3 interacted with Dnmt3a promoter with increased affinity, facilitating Dnmt3a transcription. Ectopic application of circ-Amotl1 accelerating wound repair may shed light on skin wound healing clinically.
Yang et al. show that expression of the circular RNA circ-Amotl1 accelerated wound healing and increased levels of Stat3 and Dnmt3a. The increased Dnmt3a methylated miR-17 promoter, decreasing miR-17-5p levels but increasing fibronectin expression. Furthermore, circ-Amotl1 facilitated Stat3 nuclear translocation to promote cell activities and wound repair.
Abstract Combinations of drugs promoting anti-angiogenesis and apoptosis effects are meaningful for cancer therapy. In the present study, dual peptides-modified liposomes were designed by attaching ...two receptor-specific peptides, specifically low-density lipoprotein receptor-related protein receptor (Angiopep-2) and neuropilin-1 receptor (tLyP-1) for brain tumor targeting and tumor penetration. Vascular endothelial growth factor (VEGF) siRNA and chemotherapeutic docetaxel (DTX) were chosen as the two payloads because VEGF is closely associated with angiogenesis, and DTX can kill tumor cells efficiently. Binding to glioma cells, co-delivery of siRNA and DTX in human glioblastoma cells (U87 MG) and murine brain microvascular endothelial cells (BMVEC), VEGF gene silencing, antiproliferation and anti-tumor effects of the dual peptides-modified liposomes were evaluated in vitro and in vivo . The dual peptides-modified liposomes persisted the binding ability to glioma cells, enhanced the internalization via specific receptor mediated endocytosis and tissue penetration, thus the dual peptides-modified liposomes loading VEGF siRNA and DTX possessed stimulative gene silencing and antiproliferation activity compared with non-modified and single peptide-modified liposomes. The co-delivery research revealed different intracellular behavior of hydrophilic large molecular and lipophilic small molecule, the former involves endocytosis and subsequent escape of endosome/lysosomes, while the latter experiences passive diffusion of lipophilic small drugs after its release. Furthermore, the dual peptides-modified liposomes showed superiority in anti-tumor efficacy, combination of anti-angiogenesis by VEGF siRNA and apoptosis effects by DTX, after both intratumor and system application against mice with U87 MG tumors, and the treatment did not activate system-associated toxicity or the innate immune response. Combination with the dual peptides-guided tumor homing and penetration, the dual peptides-modified liposomes provide a strategy for effective targeting delivery of siRNA and DTX into the glioma cell and inhibition of tumor growth in a synergistic manner.
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