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A major hurdle in the treatment of cancer is chemoresistance induced under hypoxia that is characteristic of tumor microenvironment. Triptolide, a potent inhibitor of eukaryotic transcription, possesses potent antitumor activity. ...
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A major hurdle in the treatment of cancer is chemoresistance induced under hypoxia that is characteristic of tumor microenvironment. Triptolide, a potent inhibitor of eukaryotic transcription, possesses potent antitumor activity. However, its clinical potential has been limited by toxicity and water solubility. To address those limitations of triptolide, we designed and synthesized glucose-triptolide conjugates (glutriptolides) and demonstrated their antitumor activityin?vitroandin?vivo. Herein, we identified a lead, glutriptolide-2 with an altered linker structure. Glutriptolide-2 possessed improved stability in human serum, greater selectivity toward cancer over normal cells, and increased potency against cancer cells. Glutriptolide-2 exhibits sustained antitumor activity, prolonging survival in a prostate cancer metastasis animal model. Importantly, we found that glutriptolide-2 was more potent against cancer cells under hypoxia than normoxia. Together, this work provides an attractive glutriptolide drug lead and suggests a viable strategy to overcome chemoresistance through conjugation of cytotoxic agents to glucose.
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Advances in the chemical synthesis of C-pyranosides/furanosides are summarized, covering the literature from 2000 to 2016. The majority of the methods take advantage of the construction of the glycosidic C—C bond. These C-glycosy...
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Advances in the chemical synthesis of C-pyranosides/furanosides are summarized, covering the literature from 2000 to 2016. The majority of the methods take advantage of the construction of the glycosidic C—C bond. These C-glycosylation methods are categorized herein in terms of the glycosyl donor precursors, which are commonly used in O-glycoside synthesis and are easily accessible to nonspecialists. They include glycosyl halides, glycals, sugar acetates, sugar lactols, sugar lactones, 1,2-anhydro sugars, thioglycosides/sulfoxides/sulfones, selenoglycosides/telluroglycosides, methyl glycosides, and glycosyl imidates/phosphates. Mechanistically, C-glycosylation reactions can involve glycosyl electrophilic/cationic species, anionic species, radical species, or transition-metal complexes, which are discussed as subcategories under each type of sugar precursor. Moreover, intramolecular rearrangements, such as the Claisen rearrangement, Ramberg–B?cklund rearrangement, and 1,2-Wittig rearrangement, which usually involve concerted pathways, constitute another category of C-glycosylations. An alternative to the C-glycosylations is the formation of pyranoside/furanoside rings after construction of the predetermined glycosidic C—C bonds, which might involve cyclization of acyclic precursors or D–A cycloadditions. Throughout, the stereoselectivity in the formation of the resultant C-glycosidic linkages is highlighted.]]>
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Carbohydrates are fundamental molecules involved in nearly all aspects of lives, such as being involved in formating the genetic and energy materials, supporting the structure of organisms, constituting invasion and host defense s...
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Carbohydrates are fundamental molecules involved in nearly all aspects of lives, such as being involved in formating the genetic and energy materials, supporting the structure of organisms, constituting invasion and host defense systems, and forming antibiotics secondary metabolites. The naturally occurring carbohydrates and their derivatives have been extensively studied as therapeutic agents for the treatment of various diseases. During 2000 to 2021, totally 54 carbohydrate-based drugs which contain carbohydrate moities as the major structural units have been approved as drugs or diagnostic agents. Here we provide a comprehensive review on the chemical structures, activities, and clinical trial results of these carbohydrate-based drugs, which are categorized by their indications into antiviral drugs, antibacterial/antiparasitic drugs, anticancer drugs, antidiabetics drugs, cardiovascular drugs, nervous system drugs, and other agents.
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Chitin is the second most abundant organic compound after cellulose in nature, which exists mainly as a structural component of the exoskeletons of insects and crustaceans as well as of the cell walls of bacteria and fungi. As an ...
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Chitin is the second most abundant organic compound after cellulose in nature, which exists mainly as a structural component of the exoskeletons of insects and crustaceans as well as of the cell walls of bacteria and fungi. As an important marine biomass resource, chitin is estimated to be produced in 1e100 billion metric tons annually. Structurally, chitin is a linear polysaccharide composed of β-(1→4) linked 2-acetamido-2-deoxy-D-glucopyranose (GlcNAc) monosaccharide repeating units, so that it could be considered as cellulose derivative by replacing the C2 hydroxyl groups of cellulose with acetamide groups (Fig. 1). Chitosan is partially N-deacetylated chitin, thus it is a linear copolymer of randomly distributed 2-amido-2-deoxy-D-glucopyranose (GlcN) and GlcNAc units through β-(1→4) glycosidic linkages. As a characteristic parameter of polymer, the molecular weight of the native chitin can reach up to several million Daltons while commercial chitosan has a molecular weight ranging from 50 kDa to 2000 kDa.
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Histone H3 is phosphorylated at Ser10 by multiple kinases, and many of them are anti-cancer targets. Here, we report the first kinase that can phosphorylate H3Ser10 in both interphase and mitosis, which we named KimH3 (kinase of i...
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Histone H3 is phosphorylated at Ser10 by multiple kinases, and many of them are anti-cancer targets. Here, we report the first kinase that can phosphorylate H3Ser10 in both interphase and mitosis, which we named KimH3 (kinase of interphase and mitotic Histone H3). Meta-analysis indicates that KimH3 is upregulated in a broad spectrum of human cancers and its high expression is correlated with reduced the median survival time of cancer patients. In mitosis, CDK1 phosphorylates KimH3, which then phosphorylates H3Ser10 to regulate cell cycle procession. In interphase, EGF induces KimH3 activation and H3Ser10 phosphorylation, which is involved in MAPK-ERK1/2 signaling pathway to activate immediate-early genes transcription. Consequently, a small molecule inhibitor of KimH3 significantly inhibited tumor growth in mice. This is not only consistent with the dual roles of KimH3 in both interphase and mitotic Histone H3 phosphorylation, but also reveals it as an important potential anti-cancer target.
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Nanomedicines with controlled drug release have received increasing attention as an advanced therapeutic strategy for bone diseases. To traverse biological barriers towards pathological site of bone and endow drug release with spa...
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Nanomedicines with controlled drug release have received increasing attention as an advanced therapeutic strategy for bone diseases. To traverse biological barriers towards pathological site of bone and endow drug release with spatial, temporal and dose controllability, the design of nanocarriers based on bone micro-environment and their pathological changes during diseases is an attractive idea. Distinguishable biological, physical and chemical features of the bone pathological microenvironment can be exploited to develop targeted and stimuli-responsive nanocarriers thus maximizing the effective enrichment of drugs in the pathological microenvironment. Herein, we present a review of bone targeting strategies based on the characteristics of the bone microenvironment, their pathological changes during bone diseases and corresponding strategies for the construction of stimuli-responsive nanocarriers. The available stimuli in the context of bone disease, design principles of stimuli-responsive delivery systems and recent advances in their application for bone therapy were highlighted. Thereby, the emerging new concept, that is, the bone microenvironment-responsive drug delivery system, was systematically illustrated. Furthermore, the challenges and future prospects of such smart drug delivery systems for bone therapy applications are discussed.
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In this paper, an efficient mechatronic approach is used to integrate various components of a robot system interacting with an external environment. Both hardware and software integration are considered in the development of the o...
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In this paper, an efficient mechatronic approach is used to integrate various components of a robot system interacting with an external environment. Both hardware and software integration are considered in the development of the open-architecture experimental platform. Real-time control software is developed to provide optimal use of the hardware components and available processing capability. Extensive experiments for a surface following robot task are conducted using the experimental platform. Emphasis is given to two important aspects, rate of sampling and data filtering. To minimize feedback and control algorithm switching delays, various modes of operation that involve efficient data communication and data filtering are considered and compared via experiments. Applications of the developed experimental platform include robotic surface following and surface finishing operations.
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Saikosaponin A (SSa) and D (SSd) are typical oleanane-type saponins featuring a unique 13,28-epoxy-ether moiety at D ring of the aglycones, which exhibit a wide range of biological and pharmacological activities. Herein, we report...
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Saikosaponin A (SSa) and D (SSd) are typical oleanane-type saponins featuring a unique 13,28-epoxy-ether moiety at D ring of the aglycones, which exhibit a wide range of biological and pharmacological activities. Herein, we report the first synthesis of saikosaponin A/D (1–2) and their natural congeners, including prosaikosaponin F (3), G (4), saikosaponin Y (5), prosaikogenin (6), and clinoposaponin I (7). The present synthesis features ready preparation of the aglycones of high oxidation state from oleanolic acid, regioselective glycosylation to construct the β-(1→3)-linked disaccharide fragment, and efficient gold(I)-catalyzed glycosylation to install the glycans on to the aglycones.
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The pleiotropic action of adiponectin in improving cell survival and metabolism has motivated the development of small molecule therapeutic agents for treating diabetes and lipotoxicity. AdipoRon is a synthetic agonist of adiponec...
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The pleiotropic action of adiponectin in improving cell survival and metabolism has motivated the development of small molecule therapeutic agents for treating diabetes and lipotoxicity. AdipoRon is a synthetic agonist of adiponectin receptor yet is limited by its poor solubility and bioavailability. In this work, we expand on the protective effects of AdipoRon in pancreatic β-cells and examine how structural modifications could affect the activity, pharmacokinetics, and bioavailability of this small molecule. We describe a series of AdipoRon analogs containing amphiphilic ethylene glycol (PEG) chains. Among these, AdipoRonPEG5 induced pleiotropic effects in mice under insulinopenic and high fat diet (HFD) conditions. While both AdipoRon and AdipoRonPEG5 substantially attenuate palmitate-induced lipotoxicity in INS-1 cells, only AdipoRonPEG5 treatment is accompanied by a significant reduction in cytotoxic ceramides. In vivo, AdipoRonPEG5 can substantially reduce pancreatic, hepatic, and serum ceramide species, with a concomitant increase in the corresponding sphingoid bases, and improves insulin sensitivity of mice under HFD feeding conditions. Furthermore, hyperglycemia in streptozotocin (STZ)-induced insulinopenic adiponectin-null mice is also attenuated upon AdipoRonPEG5 treatment. Our results suggest that AdipoRonPEG5 is more effective in reducing ceramides and dihydroceramides in the liver of HFD-fed mice than AdipoRon, consistent with its potent activity in activating ceramidase in vitro in INS-1 cells. Additionally, these results indicate that the beneficial effects of AdipoRonPEG5 can be partially attributed to improved pharmacokinetics as compared to AdipoRon, thus suggesting that further derivatization may improve affinity and tissue-specific targeting.Copyright ? 2021 The Authors. Published by Elsevier Inc. All rights reserved.
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In recent years, membrane technologies have been developed to address water shortage and energy crisis. Forward osmosis (FO), as an emerging membrane-based water treatment technology, employs an extremely concentrated draw solutio...
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In recent years, membrane technologies have been developed to address water shortage and energy crisis. Forward osmosis (FO), as an emerging membrane-based water treatment technology, employs an extremely concentrated draw solution (DS) to draw water pass through the semi-permeable membrane from a feed solution. DS as a critical material in FO process plays a key role in determining separation performance and energy cost. Most of existing DSs after FO still require a regeneration step making its return to initial state. Therefore, selecting suitable DS with low reverse solute, high flux, and easy regeneration is critical for improving FO energy efficiency. Numerous novel DSs with improved performance and lower regeneration cost have been developed. However, none reviews reported the categories of DS based on the energy used for recovery up to now, leading to the lack of enough awareness of energy consumption in DS regeneration. This review will give a comprehensive overview on the existing DSs based on the types of energy utilized for DS regeneration. DS categories based on different types of energy used for DS recovery, mainly including direct use based, chemical energy based, waste heat based, electric energy based, magnetic field energy based, and solar energy based are proposed. The respective benefits and detriments of the majority of DS are addressed respectively according to the current reported literatures. Finally, future directions of energy applied to DS recovery are also discussed.
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