Zinc homeostatic medicine is of great potential for cancer chemo‐immunotherapy; however, there are few reports on antitumor compounds that can trigger Zn2+‐mediated immune responses. In this work, we ...developed a novel cyclometalated PtIV‐terthiophene complex, Pt3, that not only induces DNA damage and cellular metabolism dysregulation, but also disrupts zinc homeostasis as indicated by the abnormal transcriptional level of zinc regulatory proteins, excess accumulation of Zn2+ in cytoplasm, and down‐regulation of metallothioneins (MTs), which further caused redox imbalance. The simultaneous disruption of zinc and redox homeostasis in response to Pt3 treatment activated gasdermin‐D mediated pyroptosis accompanied by cytoskeleton remodeling, thus releasing pro‐inflammatory cytokines to promote dendritic cell (DC) maturation and T cell tumor‐infiltration, eventually eliminating both primary and distant tumors in vivo. As far as we know, this is the first metal complex that can regulate zinc homeostasis to activate antitumor immunity.
We developed a novel cyclometalated PtIV‐terthiophene complex as the first metal‐based zinc homeostatic medicine that regulates zinc homeostasis to activate antitumor immunity.
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•Key biological factors related to drug resistance, toxicity and side effects.•Important antitumor targets and their corresponding inhibitors/targeting groups.•Specific-targeted ...platinum complexes to overcome those problems.•Immune response therapy and tumor microenvironment regulation as burgeoning strategies.•Up-to-date advances in light responsive stimulation and theranostic therapy.
Encouraged by the worldwide success of cisplatin in the field of cancer chemotherapy, intensive works have been conducted to explore more platinum coordination complexes as antitumor drugs over half a century. Although a significant number of promising platinum complexes with multiple structural motifs have been emerging during this period, most of them failed to enter clinical applications. Abandoned reasons for platinum antitumor candidates from experiment to clinic are complicated, and corresponding strategies were proposed during the last decades to deal with those issues. In recent years, with the rapid development of targeted therapy, immunotherapy and so on, anticancer platinum drugs have gained new opportunities and challenges. In this review, we first overviewed the major problems associated with current platinum anticancer drugs including drug resistance, toxicity and side effects to “know our enemies”, and then described recent progresses in rational design of specific-targeted platinum complexes, immune response therapy, tumor microenvironment regulation, light-responsive stimulation, and theranostic therapy as promising strategies to cross these barriers. This review at the interface of chemistry, biology, and medicine points out main problems for current platinum drug development from their action mechanisms, and provides up-to-date potential strategies from drug design perspectives to circumvent those drawbacks, and it is supposed to enlighten researchers with more ideas for future development of highly efficient platinum antitumor complexes.
G‐quadruplexes (G4s) are prevalent in oncogenes and are potential antitumor drug targets. However, binding selectivity of compounds to G4s still faces challenges. Herein, we report a platinum(II) ...complex (Pt1), whose affinity to G4‐DNA is activated by adaptive binding and selectivity controlled by binding kinetics. The resolved structure of Pt1/VEGF‐G4 (a promoter G4) shows that Pt1 matches 3′‐G‐tetrad of VEGF‐G4 through Cl−‐dissociation and loop rearrangement of VEGF‐G4. Binding rate constants are determined by coordination bond breakage/formation, correlating fully with affinities. The selective rate‐determining binding step, Cl−‐dissociation upon G4‐binding, is 2–3 orders of magnitude higher than dsDNA. Pt1 potently targets G4 in living cells, effectively represses VEGF expression, and inhibits vascular growth in zebrafish. We show adaptive G4‐binding activation and controlled by kinetics, providing a complementary design principle for compounds targeting G4 or similar biomolecules.
A PtII compound was synthesized and adaptively bound G‐quadruplex DNA through kinetic control. The solution structure of the complex was solved. It was further proved that the compound can target G‐quadruplex in living cells, repress VEGF expression in cancer cells and inhibit blood vessels growth in zebrafish.
Abstract
Chemical modification of transcripts with 5′ caps occurs in all organisms. Here, we report a systems-level mass spectrometry-based technique, CapQuant, for quantitative analysis of an ...organism's cap epitranscriptome. The method was piloted with 21 canonical caps—m7GpppN, m7GpppNm, GpppN, GpppNm, and m2,2,7GpppG—and 5 ‘metabolite’ caps—NAD, FAD, UDP-Glc, UDP-GlcNAc, and dpCoA. Applying CapQuant to RNA from purified dengue virus, Escherichia coli, yeast, mouse tissues, and human cells, we discovered new cap structures in humans and mice (FAD, UDP-Glc, UDP-GlcNAc, and m7Gpppm6A), cell- and tissue-specific variations in cap methylation, and high proportions of caps lacking 2′-O-methylation (m7Gpppm6A in mammals, m7GpppA in dengue virus). While substantial Dimroth-induced loss of m1A and m1Am arose with specific RNA processing conditions, human lymphoblast cells showed no detectable m1A or m1Am in caps. CapQuant accurately captured the preference for purine nucleotides at eukaryotic transcription start sites and the correlation between metabolite levels and metabolite caps.
Our study aimed to investigate the short‐term efficacy and long‐term prognosis of liver failure patients caused by hepatitis B after a single transplantation with autologous marrow mesenchymal stem ...cells (MMSCs). A total of 527 inpatients with liver failure caused by hepatitis B were recruited and received the same medical treatments, among whom 53 patients underwent a single transplantation with autologous MMSCs. A total of 105 patients matched for age, sex, and biochemical indexes, including alanine aminotransferase (ALT), albumin, total bilirubin (TBIL), prothrombin time (PT), and Model for End‐Stage Liver Disease (MELD), comprised the control group. A total of 120 mL of bone marrow was obtained from each patient and then diluted and separated. Then, the MMSC suspension was slowly transfused into the liver through the proper hepatic artery. The success rate of transplantation was 100%, without serious side effects or complications. Levels of ALB, TBIL, and PT and MELD score of patients in the transplantation group were markedly improved from 2‐3 weeks after transplantation, compared with those in the control group. At 192 weeks of follow‐up, there were no dramatic differences in incidence of hepatocellular carcinoma (HCC) or mortality between the two groups. Additionally, there were no significant differences in the incidence of HCC or mortality between patients with and without cirrhosis in the transplantation group. Conclusion: Autologous MMSC transplantation is safe for liver failure patients caused by chronic hepatitis B. Short‐term efficacy was favorable, but long‐term outcomes were not markedly improved. In respect to several parameters, this method is preferable for patients with liver cirrhosis and may have potential for reducing their incidence of HCC and mortality. (HEPATOLOGY 2011;)
Abstract
Regulating autophagy to control the homeostatic recycling process of cancer cells is a promising anticancer strategy. Golgi apparatus is a substrate of autophagy but the Golgi‐autophagy ...(Golgiphagy) mediated antitumor pathway is rarely reported. Herein, we have developed a novel Golgi‐targeted platinum (II) complex
Pt3
, which is ca. 20 times more cytotoxic to lung carcinoma than cisplatin and can completely eliminate tumors after intratumoral administration in vivo. Its nano‐encapsulated system for tail vein administration also features a good anti‐tumor effect. Mechanism studies indicate that
Pt3
induces substantial Golgi stress, indicated by the fragmentation of Golgi structure, down‐regulation of Golgi proteins (GM130, GRASP65/55), loss of Golgi‐dependent transport and glycosylation. This triggers Golgiphagy but blocks the subsequent fusion of autophagosomes with lysosomes, that is a dual role in autophagy regulation, resulting in loss of proteostasis and apoptotic cell death. As far as we know,
Pt3
is the first Golgi‐targeted Pt complex that can trigger Golgi stress‐mediated dual‐regulation of autophagic flux and autophagy‐apoptosis crosstalk for highly efficient cancer therapy.
A range of indolizine smoothly underwent visible-light-induced intermolecular 3+2 annulations with internal alkynes to afford pyrrolo2,1,5-cdindolizine in good to excellent yields with high ...regioselectivity. Through this cascade reaction, a series of fluoroactive fused indolizines with a large π-system were conveniently synthesized. The usage of visible light as energy source with air as a stoichiometric oxidant under simple conditions makes this process attractive and practical.
Magnesium (Mg) is the fourth most abundant element in the human body and is important in terms of specific osteogenesis functions. Here, we provide a comprehensive review of the use of ...magnesium-based biomaterials (MBs) in bone reconstruction. We review the history of MBs and their excellent biocompatibility, biodegradability and osteopromotive properties, highlighting them as candidates for a new generation of biodegradable orthopedic implants. In particular, the results reported in the field-specific literature (280 articles) in recent decades are dissected with respect to the extensive variety of MBs for orthopedic applications, including Mg/Mg alloys, bioglasses, bioceramics, and polymer materials. We also summarize the osteogenic mechanism of MBs, including a detailed section on the physiological process, namely, the enhanced osteogenesis, promotion of osteoblast adhesion and motility, immunomodulation, and enhanced angiogenesis. Moreover, the merits and limitations of current bone grafts and substitutes are compared. The objective of this review is to reveal the strong potential of MBs for their use as agents in bone repair and regeneration and to highlight issues that impede their clinical translation. Finally, the development and challenges of MBs for transplanted orthopedic materials are discussed.
The conversion of skeletal muscle fiber from fast twitch to slow‐twitch is important for sustained and tonic contractile events, maintenance of energy homeostasis, and the alleviation of fatigue. ...Skeletal muscle remodeling is effectively induced by endurance or aerobic exercise, which also generates several tricarboxylic acid (TCA) cycle intermediates, including succinate. However, whether succinate regulates muscle fiber‐type transitions remains unclear. Here, we found that dietary succinate supplementation increased endurance exercise ability, myosin heavy chain I expression, aerobic enzyme activity, oxygen consumption, and mitochondrial biogenesis in mouse skeletal muscle. By contrast, succinate decreased lactate dehydrogenase activity, lactate production, and myosin heavy chain IIb expression. Further, by using pharmacological or genetic loss‐of‐function models generated by phospholipase Cβ antagonists, SUNCR1 global knockout, or SUNCR1 gastrocnemius‐specific knockdown, we found that the effects of succinate on skeletal muscle fiber‐type remodeling are mediated by SUNCR1 and its downstream calcium/NFAT signaling pathway. In summary, our results demonstrate succinate induces transition of skeletal muscle fiber via SUNCR1 signaling pathway. These findings suggest the potential beneficial use of succinate‐based compounds in both athletic and sedentary populations.
Synopsis
Aerobic exercise leads to skeletal muscle remodelling. This study reveals that dietary succinate is sufficient to elicit muscle remodelling and increased endurance in sedentary mice.
Dietary succinate increases endurance exercise ability in mice.
Dietary succinate induces skeletal muscle fiber transition from fast‐twitch to slow‐twitch.
SUNCR1 signaling pathway is required for the succinate induced skeletal muscle remodeling.
Aerobic exercise leads to skeletal muscle remodelling. This study reveals that dietary succinate is sufficient to elicit muscle remodelling and increased endurance in sedentary mice.
Production of more than 20 million tons of epoxides per year from olefins suffers from low atom economy due to the use of oxidants and complex catalysts with unsatisfactory selectivity, leading to ...huge environmental and economic costs. We present a proof‐of‐concept application of electron‐rich RuO2 nanocrystals to boost the highly selective epoxidation of cyclooctene via direct oxygen transfer from water as the sole oxygen source under mild conditions. The enhanced electron enrichment of RuO2 nanocrystals via the Schottky effect with nitrogen‐doped carbons largely promotes the capture and activation of cyclooctene to give a high turnover frequency (260 h−1) of cyclooctene oxide, far surpassing the reported values (<20 h−1) of benchmarked catalysts at room temperature with oxidants. Our electron‐rich RuO2 electrocatalysts enable efficient and durable hydrogen production (Faradaic efficiency >90 %) on the cathode without impacting on the selectivity to epoxide (>99 %) on the anode.
Electron enrichment of metallic RuO2 nanocrystals can boost the highly selective epoxidation of cyclooctene via direct oxygen transfer from sustainable water, which is the sole oxygen source under ambient conditions. An efficient hydrogen evolution reaction is also enabled on the counter cathode without sacrificing the high selectivity to epoxide on the working electrode.
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