Current therapy of malignant glioma in clinic is unsatisfactory with poor patient compliance due to low therapeutic efficiency and strong systemic side effects. Herein, we combined chemo-photothermal targeted therapy of glioma within one novel multifunctional drug delivery system. A targeting peptide (IP)-modified mesoporous silica-coated graphene nanosheet (GSPI) was successfully synthesized and characterized, and first introduced to the drug delivery field. A doxorubicin (DOX)-loaded GSPI-based system (GSPID) showed heat-stimulative, pH-responsive, and sustained release properties. Cytotoxicity experiments demonstrated that combined therapy mediated the highest rate of death of glioma cells compared to that of single chemotherapy or photothermal therapy. Furthermore, the IP modification could significantly enhance the accumulation of GSPID within glioma cells. These findings provided an excellent drug delivery system for combined therapy of glioma due to the advanced chemo-photothermal synergistic targeted therapy and good drug release properties of GSPID, which could effectively avoid frequent and invasive dosing and improve patient compliance.
LPS-activated macrophages undergo a metabolic shift from dependence on mitochondria-produced ATP to reliance on aerobic glycolysis, where PKM2 is a critical determinant. Here, we show that PKM2 is a physiological substrate of SIRT5 and that SIRT5-regulated hypersuccinylation inhibits the pyruvate kinase activity of PKM2 by promoting its tetramer-to-dimer transition. Moreover, a succinylation-mimetic PKM2 K311E mutation promotes nuclear accumulation and increases protein kinase activity. Furthermore, we show that SIRT5-dependent succinylation promotes PKM2 entry into nucleus, where a complex of PKM2-HIF1α is formed at the promoter of IL-1β gene in LPS-stimulated macrophages. Activation of PKM2 using TEPP-46 attenuates Sirt5-deficiency-mediated IL-1β upregulation in LPS-stimulated macrophages. Finally, we find that Sirt5-deficient mice are more susceptible to DSS-induced colitis, which is associated with Sirt5 deficiency prompted PKM2 hypersuccinylation and boosted IL-1β production. In conclusion, our findings reveal a mechanism by which SIRT5 suppresses the pro-inflammatory response in macrophages at least in part by regulating PKM2 succinylation, activity, and function.
In the past decades, drug delivery systems (DDSs) based on nanotechnology have been studied extensively to overcome the nonselectivity of chemotherapy, to avoid damaging healthy tissues, and to improve cancer cure rates. [1][2][3] A practical DDS should possess the two general characteristics of specific targeting and controllable release. With regard to specific targeting, it is widely accepted that nanocarriers are able to enter cells rapidly through intracellular endocytic pathways [4] and effectively release drugs at target sites. With regard to controllable release, different responding agents or conditions have been employed, such as pH, [5] temperature, [6] enzyme, [7,8] biomolecules [9,10] and light. [11][12][13] Among these, pH-responsive DDSs have shown great advantages as a result of their simple design and universal applicability, because pH values in tumors and inflammatory tissues are significantly lower than those in blood and normal tissues. [14][15][16] The pH-responsive systems usually employ pH-sensitive linkers, [17] pH-responsive polymeric micelles, [18] pH-tunable calcium phosphate, [19] etc. For instance, pH-responsive molecules [20] or ZnO nanoparticles [21] can be used as cappers to cover the pores of mesoporous silica nanoparticles (MSNs). However, the strong adsorption ability of MSNs hinders the complete release of the drug and the biodegradability of MSNs also remains a controversial problem. [22] As we reported previously, these problems cannot be resolved by using nanocarriers based on carbon nanotubes and mesoporous carbon materials. [23,24] As a cheap nanomaterial with low toxicity, ZnO quantum dots (QDs) have shown great potential for application in bioimaging. [25][26][27][28] Because the unprotected ZnO QDs are decomposed completely at pH 5 in aqueous solution, these materials can be employed as nanocarriers for drug delivery. Herein, we synthesized biodegradable ZnO@polymer coreshell QDs with excellent water solubility, biocompatibility, and pH sensitivity as drug carriers in order to study the release process and activity in vitro. Polyacrylamide, which is nontoxic to animals, [29] was used as a protecting shell for the ZnO QDs. The well-known doxorubicin hydrochloride (DOX) was selected as anticancer drug because its clinical application has so far been hampered by nonselective biodistribution and severe damage to healthy tissues. [30] Furthermore, human glioblastoma cells (U251), the most common cells in malignancies of the human brain, [31] were chosen as model cells. DOX is a hydrophilic molecule and its ability to pass through biological barriers such as the bloodbrain barrier is rather weak, hence treatment of brain tumors with DOX remains a challenge. [32] After they were loaded with DOX, our ZnO@polymer QDs crossed the cell membrane through a cellular uptake pathway, decomposed at the endosomes or lysosomes to release DOX molecules, which finally penetrated into the nuclei to kill the cells. This process and the drug release mechanism were proven by direct observation...
Cancer imaging requires biocompatible and bright contrast-agents with selective and high accumulation in the tumor region but low uptake in normal tissues. Herein, 1-methyl-2-pyrrolidinone (NMP)-derived polymer-coated nitrogen-doped carbon nanodots (pN-CNDs) with a particle size in the range of 5-15 nm are prepared by a facile direct solvothermal reaction. The as-prepared pN-CNDs exhibit stable and adjustable fluorescence and excellent water solubility. Results of a cell viability test (CCK-8) and histology analysis both demonstrate that the pN-CNDs have no obvious cytotoxicity. Most importantly, the pN-CNDs can expediently enter glioma cells in vitro and also mediate glioma fluorescence imaging in vivo with good contrast via elevated passive targeting.
It is a major question in archaeology and anthropology whether human populations started to grow primarily after the advent of agriculture, i.e., the Neolithic time, especially in East Asia, which was one of the centers of ancient agricultural civilization. To answer this question requires an accurate estimation of the time of lineage expansion as well as that of population expansion in a population sample without ascertainment bias. In this study, we analyzed all available mtDNA genomes of East Asians ascertained by random sampling, a total of 367 complete mtDNA sequences generated by the 1000 Genome Project, including 249 Chinese (CHB, CHD, and CHS) and 118 Japanese (JPT). We found that major mtDNA lineages underwent expansions, all of which, except for two JPT-specific lineages, including D4, D4b2b, D4a, D4j, D5a2a, A, N9a, F1a1'4, F2, B4, B4a, G2a1 and M7b1'2'4, occurred before 10 kya, i.e., before the Neolithic time (symbolized by Dadiwan Culture at 7.9 kya) in East Asia. Consistent to this observation, the further analysis showed that the population expansion in East Asia started at 13 kya and lasted until 4 kya. The results suggest that the population growth in East Asia constituted a need for the introduction of agriculture and might be one of the driving forces that led to the further development of agriculture.
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