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Inducing protein degradation by proteolysis targeting chimeras has gained tremendous momentum as a promising novel therapeutic strategy. Here, we report the design, synthesis, and biological characterization of highly potent proteolysis targeting chimeric small molecules targeting the epigenetic regulator histone deacetylase 8 (HDAC8). We developed potent and effective HDAC8 degraders, as exemplified by

Renal microvascular endothelial cells (RMECs), which are closely related to regulation of vascular reactivity and modulation of inflammation, play a crucial role in the process of renal ischemia and reperfusion (I/R) injury. Previous studies have reported the protective effects of dexmedetomidine (DEX) against renal I/R injury, but little is known about the role of DEX on RMECs. This study aimed to investigate whether DEX alleviated renal I/R injury via acting on the RMECs. Mice underwent bilateral renal artery clamping for 45 min followed by reperfusion for 48 h, and the cultured neonatal mice RMECs were subjected to hypoxia for 1 h followed by reoxygenation (H/R) for 24 h. The results suggest that DEX alleviated renal I/R injury in vivo and improved cell viability of RMECs during H/R injury in vitro. Gene sequencing revealed that the PI3K/Akt was the top enriched signaling pathway and the endothelial cells were widely involved in renal I/R injury. DEX activated phosphorylation of PI3K and Akt, increased eNOS expression, and attenuated inflammatory responses. In addition, the results confirmed the distribution of α

Photodynamic therapy (PDT) leads to tumor hypoxia which could be utilized for the activation of hypoxia-activated prodrugs (HAPs). However, conventional photosensitizer-loaded nanoformulations suffer from an aggregation-caused quenching (ACQ) effect, which limits the efficiency of PDT and synergistic therapy. Herein, prodrug-nanoparticles (NPs) are prepared by the self-assembly of heterodimeric prodrugs composed of pyropheophorbide a (PPa), hypoxia-activated prodrug PR104A, and a thioether or thioketal linkage. In addition, a novel dual-modality drug release pattern is proposed on the basis of the structural states of prodrug-NPs. Under light irradiation, PR104A is released via photoinduced electron transfer (PET) due to the aggregation state of prodrugs. With the disassembly of prodrug-NPs, the ACQ effect is relieved, and PPa produces singlet oxygen which further promotes the reactive oxygen species (ROS)-sensitive release of PR104A. Such prodrug-NPs turn the disadvantage of the ACQ effect to facilitate drug release, demonstrating high-efficiency synergy in combination with PDT and hypoxia-activated therapy.

Purpose: Apoptosis induced by excessive endoplasmic reticulum (ER) stress is accompanied by the occurrence and progression of myocardial ischemia/reperfusion (I/R) injury. COX-2 is also known to affect the development of I/R damage in myocardium. However, the interaction between COX-2 and ER stress in aggravating myocardial I/R lesion is not well characterized. Therefore, the purpose of our research was to explore the interaction between COX-2 and ER stress on myocardial apoptosis. Methods: The left anterior descending (LAD) coronary artery was ligatured with a 6-0# suture for 0.5 hours and subsequently subjected to reperfusion for 3 hours to simulate myocardial I/R in mice. Oxygen glucose deprivation/reoxygenation (OGD/R) was performed on H9c2 cells to construct an in vitro model of this experiment. NS398 (COX-2 specific inhibitor) and Salubrinal (Sal, ER stress inhibitor) were administered to assess the function of COX-2 and ER stress in myocardial I/R impairment. CCK-8 assay was used to evaluate the viability of H9c2 cells under different treatment conditions. TUNEL and Hoechst staining were used to detect the occurrence of apoptosis. Infarct area/area at risk and Hematoxylin-eosin stained sections were assessed after I/R. Protein expressions of glucose-regulated protein 78 (GRP78), COX-2, phosphorylation of eukaryotic translation initiation factor 2 alpha (p-eIF2α), CCAAT/enhancer-binding protein homologous protein (CHOP), and Cleaved caspase 3 in the myocardium were examined using Western blotting. Changes in Cleaved caspase 3 expression in myocardial slices were measured by immunohistochemistry. Results: Sal or NS398 partly reduced I/R-induced damage as testified by the apparent decrease in infarct size after I/R and reduced cell viability following OGD/R. Sal distinctly increased p-eIF2α, but caused decreased expression of COX-2, Cleaved caspase 3, and ER stress-associated proteins after I/R, suggesting that Sal effectively inhibited ER stress, apoptosis, and COX-2. Pretreatment with NS398 blocked I/R or OGD/R-induced upregulation of COX-2, Cleaved caspase 3, and ER stress-related marker proteins. Conclusions: Interaction of COX-2 and ER stress regulates apoptosis and contributes to Myocardial lesion induced by I/R.

Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic lipid accumulation, which can progress to nonalcoholic steatohepatitis (NASH). Histone deacetylase Sirtuin 6 (SIRT6) regulates NAFLD by regulating metabolism-related gene expression, but an extrachromosomal role for SIRT6 in NAFLD development remains elusive. We investigated whether SIRT6 functions on NAFLD in the cytoplasm. We found that SIRT6 binds saturated fatty acids, especially palmitic acid. This binding leads to its nuclear export, where it deacetylates long-chain acyl-CoA synthase 5 (ACSL5), thereby facilitating fatty acid oxidation. High-fat diet-induced NAFLD is suppressed by ACSL5 hepatic overexpression but is exacerbated by its depletion. As confirmation, overexpression of a deacetylated ACSL5 mimic attenuated NAFLD in Sirt6 liver-specific knockout mice. Moreover, NASH-hepatic tissues from both patients and diet-fed mice exhibited significantly reduced cytoplasmic SIRT6 levels and increased ACSL5 acetylation. The SIRT6/ACSL5 signaling pathway has a critical role in NAFLD progression and might constitute an avenue for therapeutic intervention.

The unique characteristics of the tumor microenvironment (TME) could be exploited to develop antitumor nanomedicine strategies. However, in many cases, the actual therapeutic effect is far from reaching our expectations due to the notable tumor heterogeneity. Given the amplified characteristics of TME regulated by vascular disrupting agents (VDAs), nanomedicines may achieve unexpected improved efficacy. Herein, we fabricate platelet membrane-fusogenic liposomes (PML/DP&PPa), namely “platesomes”, which actively load the hypoxia-activated pro-prodrug DMG-PR104A (DP) and physically encapsulate the photosensitizer pyropheophorbide a (PPa). Considering the different stages of tumor vascular collapse and shutdown induced by a VDA combretastatin-A4 phosphate (CA4P), PML/DP&PPa is injected 3 h after intraperitoneal administration of CA4P. First, CA4P-mediated tumor hemorrhage amplifies the enhanced permeation and retention (EPR) effect, and the platesome-biological targeting further promotes the tumor accumulation of PML/DP&PPa. Besides, CA4P-induced vascular occlusion inhibits oxygen supply, followed by photodynamic therapy-caused acute tumor hypoxia. This prolonged extreme hypoxia contributes to the complete activation of DP and then high inhibitory effect on tumor growth and metastasis. Thus, such a combining strategy of artificially-regulated TME and bio-inspired platesomes pronouncedly improves tumor drug delivery and boosts tumor hypoxia-selective activation, and provides a preferable solution to high-efficiency cancer therapy.

Heterodimeric prodrug nanoparticles overcome the penetration limitations of the neighboring effect., Chemotherapeutic nanomedicines can exploit the neighboring effect to increase tumor penetration. However, the neighboring effect is limited, likely by the consumption of chemotherapeutic agents and resistance of internal hypoxic tumor cells. Here, we first propose and demonstrate that apoptotic bodies (ApoBDs) could carry the remaining drugs to neighboring tumor cells after apoptosis. To enhance the ApoBD-based neighboring effect, we fabricated disulfide-linked prodrug nanoparticles consisting of camptothecin (CPT) and hypoxia-activated prodrug PR104A. CPT kills external normoxic tumor cells to produce ApoBDs, while PR104A remains inactive. The remaining drugs could be effectively delivered into internal tumor cells via ApoBDs. Although CPT exhibits low toxicity to internal hypoxic tumor cells, PR104A could be activated to exert strong cytotoxicity, which further facilitates deep penetration of the remaining drugs. Such a synergic approach could overcome the limitations of the neighboring effect to penetrate deep into solid tumors for whole tumor destruction.

As China's first X-ray astronomical satellite, the Hard X-ray Modulation Telescope (HXMT), which was dubbed as Insight-HXMT after the launch on June 15, 2017, is a wide-band (1-250 keV) slat-collimator-based X-ray astronomy satellite with the capability of all-sky monitoring in 0.2-3 MeV. It was designed to perform pointing, scanning and gamma-ray burst (GRB) observations and, based on the Direct Demodulation Method (DDM), the image of the scanned sky region can be reconstructed. Here we give an overview of the mission and its progresses, including payload, core sciences, ground calibration/facility, ground segment, data archive, software, in-orbit performance, calibration, background model, observations and some preliminary results., 29 pages, 40 figures, 6 tables, to appear in Sci. China-Phys. Mech. Astron. arXiv admin note: text overlap with arXiv:1910.04434

Decitabine (DAC), a potent DNA methyltransferase (DNMT) inhibitor, has a limited oral bioavailability. Its 5'-amino acid ester prodrugs could improve its oral delivery but the specific absorption mechanism is not yet fully understood. The aim of this present study was to investigate the in vivo absorption and activation mechanism of these prodrugs using in situ intestinal perfusion and pharmacokinetics studies in rats. Although PEPT1 transporter is pH dependent, there appeared to be no proton cotransport in the perfusion experiment with a preferable transport at pH 7.4 rather than pH 6.5. This suggested that the transport was mostly dependent on the dissociated state of the prodrugs and the proton gradient might play only a limited role. In pH 7.4 HEPES buffer, an increase in Peff was observed for L-val-DAC, D-val-DAC, L-phe-DAC and L-trp-DAC (2.89-fold, 1.2-fold, 2.73-fold, and 1.90-fold, respectively), compared with the parent drug. When co-perfusing the prodrug with Glysar, a known substrate of PEPT1, the permeabilities of the prodrugs were significantly inhibited compared with the control. To further investigate the absorption of the prodrugs, L-val-DAC was selected and found to be concentration-dependent and saturable, suggesting a carrier-mediated process (intrinsic Km: 7.80 ± 2.61 mM) along with passive transport. Determination of drug in intestinal homogenate after perfusion further confirmed that the metabolic activation mainly involved an intestinal first-pass effect. In a pharmacokinetic evaluation, the oral bioavailability of L-val-DAC, L-phe-DAC and L-trp-DAC were nearly 1.74-fold, 1.69-fold and 1.49-fold greater than that of DAC. The differences in membrane permeability and oral bioavailability might be due to the different stability in the intestinal lumen and the distinct PEPT1 affinity which is mainly caused by the stereochemistry, hydrophobicity and steric hindrance of the side chains. In summary, the detailed investigation of the absorption mechanism by in vivo intestinal perfusion and pharmacokinetic studies showed that the prodrugs of DAC exhibited excellent permeability and oral bioavailability, which might be attributed to a hybrid (partly PEPT1-mediated and partly passive) transport mode and a rapid activation process in enterocytes.

Graphical Abstract Unlabelled image, In the field of biomedicine, stimuli-responsive drug delivery systems (DDSs) have become increasingly popular due to their site-specific release ability in response to a certain physiological stimulus, which may result in both enhanced treatment outcome and reduced side effects. Reactive oxygen species (ROS) are the unavoidable consequence of cell oxidative metabolism. ROS play a crucial part in regulating biological and physiological processes, whereas excessive intracellular ROS usually lead to the oxidation stress which has implications in several typical diseases such as cancer, inflammation and atherosclerosis. Therefore, ROS-responsive DDSs have elicited widespread popularity for their promising applications in a series of biomedical research because the payload is only released in targeted cells or tissues that overproduce ROS. According to the design of ROS-responsive DDSs, the main release mechanisms of therapeutic agents can be ascribed to ROS-induced carrier solubility change, ROS-induced carrier cleavage or ROS-induced prodrug linker cleavage. This review summarized the latest development and novel design of ROS-responsive DDSs and discussed their design concepts and the applications in the biomedical field.

Prodrug nanoassemblies have emerged as a promising platform for the delivery of anticancer drugs. PEGylation is a "gold standard" to improve colloidal stability and pharmacokinetics of nanomedicines. However, the clinical application of PEG materials is challenged by in vivo oxidative degradation and immunogenicity. Rational design of advanced biomaterials for the surface modification of nanomedicines is the hot spot of research. Here, a zwitterionic sulfobetaine surfactant is constructed as a novel surface modifier to coassemble with 10-hydroxycamptothecin-linoleic acid conjugate, with the classical PEGylated material as control. Interestingly, both the type and ratio of surfactants have profound impacts on the molecular mechanisms of the assembly of prodrugs, thereby affecting the pharmaceutical properties. Compared with PEGylated spherical prodrug nanoassemblies, zwitterion-modified prodrug nanoassemblies have distinct rod shape and superhydrophilic surface, and exhibit potent antitumor activity due to the combination of multiple advantages in terms of colloidal stability, cellular uptake, and pharmacokinetics. The findings illustrate the crucial role of zwitterionic surfactants as the surface modifier in the determination of in vivo fate of the prodrug nanoassemblies, and pave the way for the development of advanced nanomedicines.

5-Fluorouracil (5-FU) is an antimetabolite widely used in the treatment of a variety of solid tumors. However, its clinical applications are greatly hindered by a very short residence time in blood circulation and non-specific distribution in the body. In order to overcome these challenges, 1-alkylcarbonyloxymethyl 5-FU was designed and linked with a maleimide group to form an albumin-binding 5-FU prodrug, named EMC-5-FU. In vitro incubation with bovine serum albumin (BSA) and fresh rat blood proved that the prodrug bound rapidly to cysteine-34 to form the drug–albumin conjugate nanomedicine. The conjugate BSA–EMC-5-FU was stable under acidic and neutral conditions but an unstable compound to release 5-FU in alkaline solution, and such a property was used for the determination of total 5-FU concentration in plasma. The t1/2 and AUC values of total 5-FU after an intravenous injection of EMC-5-FU to SD rats were significantly increased, about 43-fold and 93-fold higher than those of 5-FU following 5-FU intravenous administration, respectively. In vivo fluorescence images of EMC-Cy5 indirectly demonstrated the selective tumor accumulation of EMC-5-FU. In H22 tumor-bearing mice models, treatment with EMC-5-FU was more efficacious in tumor inhibition compared to 5-FU intravenous administration. In conclusion, a rapid albumin-binding prodrug strategy addresses concerns related to the poor circulation half-life and non-specific distribution of anticancer drugs, and paves the way for the development of in vivo-forming nanomedicines in clinical cancer therapy.

Tumor cells have an increased demand for amino acids to support their rapid growth and malignant metastasis. Transfer of amino acids across plasma membranes depends on several amino acid transporters that are highly upregulated in tumor cells and are promising targets for tumor cell-selective therapy. In this study, stealth liposomal systems functionalized with aspartate-polyoxyethylene stearate conjugate (APS) were developed for transporter-mediated targeted delivery to ATB0,+, which is overexpressed human lung cells. The resultant ATB0,+-targeting liposomes (APS-Lips) consisted of a liposome core and the surface coverage of the APS modifier had an optimized density of 10%. APS-Lips had a uniform particle size distribution and high encapsulation efficiency of docetaxel (DTX, >80%). APS modification had a negligible effect on the DTX release from liposomes. Compared with Taxotere and unmodified liposomes, APS-Lips showed increased intracellular delivery and antitumor potency against human lung cells. Furthermore, competitive endocytosis studies showed that the cellular uptake of APS-Lips was notably decreased in the presence of glycine, a typical substrate of ATB0,+, and was increased through adhesion to the cell membrane via transporter-substrate interactions. Finally, in vitro hemolysis and in vivo vascular irritation studies in rabbits confirmed the good blood compatibility and minimal vascular stimulation of the synthetic ATB0,+-targeting material APS. These results demonstrated that the aspartate-modified liposomes could be a promising nanocarrier for ATB0,+ transporter-mediated targeted drug delivery to treat lung cancer.

Global mean temperature is expected to be significantly higherincreased by the end of the 21st century and could have dramatic impacts on plants growth and physiology and ecosystem processes. Temperature manipulative experiments have been conducted to understand the responsive patterne of plant ecophysiology to climate warming. However, it remains unknown how different methodology conducting used in these experiments will affect plants ecophysiological responses to warming. We conducted a comprehensive meta-analysis of the warming manipulative studies to synthesize the ecophysiological traits responses to warming treatment of different intensities, durations and conducted for different species and under different experimental settings. The results indicated that warming enhanced leaf dark respiration (Rd) and specific leaf area (SLA) but decreased net photosynthetic rate (Anet) and leaf nitrogen content (LN). The positive and negative effects of warming on Rd and Anet were greater for C4 species than C3 species, respectively. The negative effect of warming treatment on Anet and LN and the positive effect on Rd were more evident under > 1 year warming treatment. Negative effects of warming were more evident for plants grown at < 10 L pots when experiment duration was longer than 1 year. The magnitude of warming treatment had a significant impact on most of the parameters that were investigated in the study. Overall, the results showed that warming effects on plant ecophysiological traits varied among different response variables and PFTs, and affected by the magnitude of temperature change and experimental methodology. The results highlight the need for cautiously selecting the values of plant ecophysiological parameters in forecasting ecosystem function changes in future climate regimes and designing controlled experiments to realistically reflecting ecosystems responses to future global warming.

The recently discovered neutron star transient Swift J0243.6+6124 has been monitored by {\it the Hard X-ray Modulation Telescope} ({\it Insight-\rm HXMT). Based on the obtained data, we investigate the broadband spectrum of the source throughout the outburst. We estimate the broadband flux of the source and search for possible cyclotron line in the broadband spectrum. No evidence of line-like features is, however, found up to $\rm 150~keV$. In the absence of any cyclotron line in its energy spectrum, we estimate the magnetic field of the source based on the observed spin evolution of the neutron star by applying two accretion torque models. In both cases, we get consistent results with $B\rm \sim 10^{13}~G$, $D\rm \sim 6~kpc$ and peak luminosity of $\rm >10^{39}~erg~s^{-1}$ which makes the source the first Galactic ultraluminous X-ray source hosting a neutron star., published

We present the X-ray timing results of the new black hole candidate (BHC) MAXI J1535-571 during its 2017 outburst from Hard X-ray Modulation Telescope (\emph{Insight}-HXMT) observations taken from 2017 September 6 to 23. Following the definitions given by \citet{Belloni2010}, we find that the source exhibits state transitions from Low/Hard state (LHS) to Hard Intermediate state (HIMS) and eventually to Soft Intermediate state (SIMS). Quasi-periodic oscillations (QPOs) are found in the intermediate states, which suggest different types of QPOs. With the large effective area of \emph{Insight}-HXMT at high energies, we are able to present the energy dependence of the QPO amplitude and centroid frequency up to 100 keV which is rarely explored by previous satellites. We also find that the phase lag at the type-C QPOs centroid frequency is negative (soft lags) and strongly correlated with the centroid frequency. By assuming a geometrical origin of type-C QPOs, the source is consistent with being a high inclination system., Comment: 12 pages, 11 figures, Sumbitted to ApJ

A primary focus of this research was to explore the activation process and mechanism of decitabine (5-aza-2′-deoxycytidine, DAC) prodrug. Recently, it has been reported that biphenyl hydrolase-like protein (BPHL) can play an important role in the activation of some amino acid nucleoside prodrugs with a general preference for hydrophobic amino acids and 5′-esters. Therefore, we put forward a bold hypothesis that this novel enzyme may be primarily responsible for the activation process of DAC prodrug as well. 5′-O-l-valyl-decitabine (l-val-DAC) was synthesized before and can be transported across biological membranes by the oligopeptide transporter (PEPT1), granting it much greater utility in vivo. In this report, l-val-DAC was found to be a good substrate of BPHL protein (K m 0.59 mM; k cat/K m 553.69 mM−1 s−1). After intestinal absorption, l-val-DAC was rapidly and almost completely hydrolyzed to DAC and l-valine. The catalysis was mainly mediated by the BPHL hydrolase and resulted in the intestinal first-pass effect of l-val-DAC after oral administration in Sprague-Dawley rats with cannulated jugular and portal veins. The structural insights using computational molecular docking showed that BPHL had a unique binding mode for l-val-DAC. As a fundamental basis, the simulation was employed to explain the catalytic mechanism in molecular level. In conclusion, BPHL was at least one of the primary candidate enzymes for L-val-DAC prodrug activation. This promising double-targeted prodrug approach have more advantages than the traditional targeted designs due to its higher transport and more predictable activation, thereby leading to a favorable property for oral delivery.

Finding the electromagnetic (EM) counterpart of binary compact star merger, especially the binary neutron star (BNS) merger, is critically important for gravitational wave (GW) astronomy, cosmology and fundamental physics. On Aug. 17, 2017, Advanced LIGO and \textit{Fermi}/GBM independently triggered the first BNS merger, GW170817, and its high energy EM counterpart, GRB 170817A, respectively, resulting in a global observation campaign covering gamma-ray, X-ray, UV, optical, IR, radio as well as neutrinos. The High Energy X-ray telescope (HE) onboard \textit{Insight}-HXMT (Hard X-ray Modulation Telescope) is the unique high-energy gamma-ray telescope that monitored the entire GW localization area and especially the optical counterpart (SSS17a/AT2017gfo) with very large collection area ($\sim$1000 cm$^2$) and microsecond time resolution in 0.2-5 MeV. In addition, \textit{Insight}-HXMT quickly implemented a Target of Opportunity (ToO) observation to scan the GW localization area for potential X-ray emission from the GW source. Although it did not detect any significant high energy (0.2-5 MeV) radiation from GW170817, its observation helped to confirm the unexpected weak and soft nature of GRB 170817A. Meanwhile, \textit{Insight}-HXMT/HE provides one of the most stringent constraints (~10$^{-7}$ to 10$^{-6}$ erg/cm$^2$/s) for both GRB170817A and any other possible precursor or extended emissions in 0.2-5 MeV, which help us to better understand the properties of EM radiation from this BNS merger. Therefore the observation of \textit{Insight}-HXMT constitutes an important chapter in the full context of multi-wavelength and multi-messenger observation of this historical GW event., Comment: accepted by Science China - Physics, Mechanics & Astronomy. Planned to publish on Oct 17, but postponed due to a problem on pdf file

Graphical Abstract Unlabelled image, A biodegradable poly(lactic-co-glycolic acid) loading atorvastatin calcium (AC) nanoparticles (AC-PLGA-NPs) were prepared by probe ultrasonication and evaporation method aiming at improving the oral bioavailability of AC. The effects of experimental parameters, including stabilizer species, stabilizer concentration and pH of aqueous phase, on particle size were also evaluated. The resultant nanoparticles were in spherical shape with an average diameter of 174.7 nm and a narrow particle size distribution. And the drug loading and encapsulation efficiency were about 8% and 71%, respectively. The particle size and polydispersion were almost unchanged in 10 days. The release curves of AC-PLGA-NPs in vitro displaying sustained release characteristics indicated that its release mechanisms were matrix erosion and diffusion. The pharmacokinetic study in vivo revealed that the Cmax and AUC0-∞ of AC-PLGA-NPs in rats were nearly 3.7-fold and 4.7-fold higher than that of pure atorvastatin calcium suspension. Our results demonstrated that the delivery of AC-PLGA-NPs could be a promising approach for the oral delivery of AC for enhanced bioavailability.

The sequences a communication system selected affect the performance of the system, so the paper focuses on the study on the correlation properties of a special sequence called hybrid bridge function sequence. Some basic concepts and classification of hybrid bridge function are presented in the paper, and the properties of hybrid bridge function sequences and their superiorities and disadvantages are presented through theoretical analysis and simulations. Finally, it can be seen that hybrid bridge function sequence is just like a bridge between bridge function sequence and Walsh sequence, so the conclusion that the hybrid bridge function’s properties are superior to Walsh sequence’s but worse than bridge function sequence’s can be obtained through the comparison of the simulation results of the communication system

Topology control algorithm for wireless Sensor Networks (WSNs) aims to adjust the network topology to improve network performance, such as throughput, connectivity and power-efficiency. In this paper, a novel adaptive topology control (ATC) method with an adjustable parameter is proposed to maximize the expected throughput and preserve connectivity and power efficiency. By tuning the adjustable parameter, ATC can reduce to most of existing topology control algorithms. Moreover, a distributed computational method is also presented to obtain the optimal adjustable parameter for maximum throughput. It is also shown that the network is of good connectivity and power efficiency under ATC with an upper bound on the adjustable parameter.