Multiple Na+ transport pathways and interfacial compatibility enable high-capacity, room-temperature quasi-solid sodium batteries.

Sodium-metal batteries (SMBs) are ideal for large-scale energy storage due to their stable operation and high capacity. However, they have safety issues caused by severe dendrite growth and side reactions, particularly when using liquid electrolytes. Therefore, it is critically important to develop electrolytes with high ionic conductivity and improved safety that are non-flammable and resistant to dendrites. Here, we developed polymerized polyethylene glycol diacrylate (PEGDA)-modified poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) electrolytes (PPEs) with highly conductive sodium bis(trifluoromethanesulfonyl)imide and corrosion-inhibitive sodium bis(oxalato)borate salts for SMBs. Well-complexed PEGDA not only increases the amorphicity of the PVDF matrix, but also offers numerous Lewis basic sites through the polar groups of carbonyl and ether groups (i.e., electron donors). The presence of the Lewis basic sites facilitates the dissociation of sodium salt and transportation of Na+ within the PVDF matrix. This results in the generation of additional Na+ transport pathways, which can enhance the performance of the battery. Among PPEs, the optimized PPE-50 exhibits a high ionic conductivity of 3.42 × 10-4 S cm-1 and a mechanical strength of 14.0 MPa. A Na||Na symmetric cell with PPE-50 displays high stability at 0.2 mA cm-2 for 800 h. PPE-50 further displays high capacity, e.g., a Na3V2(PO4)3|PPE-50|Na battery delivers a decent discharge capacity of 101.5 mAh g-1 at 1.0C after 650 cycles. Our work demonstrates the development of high-performance quasi-solid polymer electrolytes with multiple transport pathways suitable for room-temperature SMBs.

Discovery, Structure-Based Modification, In Vitro, In Vivo, and In Silico Exploration of m-Sulfamoyl Benzoamide Derivatives as Selective Butyrylcholinesterase Inhibitors for Treating Alzheimer's Disease.

For the potential therapy of Alzheimer's disease (AD), butyrylcholinesterase (BChE) has gradually gained worldwide interest in the progression of AD. This study used a pharmacophore-based virtual screening (VS) approach to identify Z32439948 as a new BChE inhibitor. Aiding by molecular docking and molecular dynamics, essential binding information was disclosed. Specifically, a subpocket was found and structure-guided design of a series of novel compounds was conducted. Derivatives were evaluated in vitro for cholinesterase inhibition and physicochemical properties (BBB, log P, and solubility). The investigation involved docking, molecular dynamics, enzyme kinetics, and surface plasmon resonance as well. The study highlighted compounds 27a (hBChE IC50 = 0.078 ± 0.03 µM) and (R)-37a (hBChE IC50 = 0.005 ± 0.001 µM) as the top-ranked BChE inhibitors. These compounds showed anti-inflammatory activity and no apparent cytotoxicity against the human neuroblastoma (SH-SY5Y) and mouse microglia (BV2) cell lines. The most active compounds exhibited the ability to improve cognition in both scopolamine- and Aß1-42 peptide-induced cognitive deficit models. They can be promising lead compounds with potential implications for treating the late stage of AD.

Development of magnetic fluorescence aptasensor for sensitive detection of saxitoxin based on Fe3O4@Au-Pt nanozymes.

In this work, on the basis of Fe3O4@Au-Pt nanozymes (MAP NZs) and aptamer recognition, a magnetic fluorescent aptasensor (MFA) was developed for sensitive and accurate detection of saxitoxin (STX). With the bridge of STX aptamer (AptSTX) and complementary DNA (cDNA), AptSTX decorated MAP NZs (MAP/Apt) and cDNA modified green quantum dots (cDNA@g-QDs) were connected to form MAP/Apt-cDNA@g-QDs complex. As STX behaves a strong binding ability towards AptSTX, it will compete with cDNA and hybridize with Apt to release cDNA@g-QDs. With the addition of TMB, MAP will catalyze TMB to the oxidized TMB (ox-TMB), thereby quenching the fluorescence of g-QDs due to the inner filter effect. Based on this finding, the quantitative relationship between the change in fluorescence of gQDs and STX concentration was explored with a limit of detection (LOD, S/N = 3) of 0.6 nM. An internal standard signal of oxTMB was adopted and reduced the fluctuation of fluorescence signal output. Besides, the fluorescence probe can selectively recognize and detect STX among five marine toxins. Eventually, the MFA method behaved good performance in detecting seafood samples with recoveries of 82.0 % âˆ¼ 102.6 % as well as coefficient of variations (CV) of 7.2 % âˆ¼ 10.3 %. Therefore, the method with internal signal is hopeful to be a potential candidate for sensitive and accurate detection of STX in seafood.

Improving Room-Temperature Li-Metal Battery Performance by In Situ Creation of Fast Li+ Transport Pathways in a Polymer-Ceramic Electrolyte.

Composite polymer-ceramic electrolytes have shown considerable potential for high-energy-density Li-metal batteries as they combine the benefits of both polymers and ceramics. However, low ionic conductivity and poor contact with electrodes limit their practical usage. In this study, a highly conductive and stable composite electrolyte with a high ceramic loading is developed for high-energy-density Li-metal batteries. The electrolyte, produced through in situ polymerization and composed of a polymer called poly-1,3-dioxolane in a poly(vinylidene fluoride)/ceramic matrix, exhibits excellent room-temperature ionic conductivity of 1.2 mS cm-1 and high stability with Li metal over 1500 h. When tested in a Li|electrolyte|LiFePO4 battery, the electrolyte delivers excellent cycling performance and rate capability at room temperature, with a discharge capacity of 137 mAh g-1 over 500 cycles at 1 C. Furthermore, the electrolyte not only exhibits a high Li+ transference number of 0.76 but also significantly lowers contact resistance (from 157.8 to 2.1 Ω) relative to electrodes. When used in a battery with a high-voltage LiNi0.8 Mn0.1 Co0.1 O2 cathode, a discharge capacity of 140 mAh g-1 is achieved. These results show the potential of composite polymer-ceramic electrolytes in room-temperature solid-state Li-metal batteries and provide a strategy for designing highly conductive polymer-in-ceramic electrolytes with electrode-compatible interfaces.

Synthesis and biological evaluation of oleanolic acid derivatives with electrophilic warheads as antitumor agents.

Aim: The oleanolic acid derivatives containing electrophilic warheads were synthesized, and their antitumor activities were investigated. Materials & methods: The cytotoxicity of compounds against tumor cells were determined by the MTT method. The antitumor effects of compounds 27a, Y03 and Y04 were evaluated in vitro through a wound-healing assay, apoptosis and cell circle analysis, and cellular reactive oxide species determination. The levels of related proteins in MCF-7 cells treated with Y03 was determined through Western blot analysis. Results & conclusion: Compounds 27a, Y03 and Y04 displayed high cytotoxicity against breast cancer cells and inhibited cell migration, induced apoptosis, arrest cell circle at G0/G1 and promoted cellular reactive oxide species generation. The antitumor mechanism involved inhibition of Akt/mTOR and induction of ferroptosis.

Functional Characterization of a (E)-ß-Ocimene Synthase Gene Contributing to the Defense against Spodoptera litura.

Soybean is a worldwide crop that offers valuable proteins, fatty acids, and phytonutrients to humans but is always damaged by insect pests or pathogens. Plants have captured sophisticated defense mechanisms in resisting the attack of insects and pathogens. How to protect soybean in an environment- or human-friendly way or how to develop plant-based pest control is a hotpot. Herbivore-induced plant volatiles that are released by multiple plant species have been assessed in multi-systems against various insects, of which (E)-ß-ocimene has been reported to show anti-insect function in a variety of plants, including soybean. However, the responsible gene in soybean is unknown, and its mechanism of synthesis and anti-insect properties lacks comprehensive assessment. In this study, (E)-ß-ocimene was confirmed to be induced by Spodoptera litura treatment. A plastidic localized monoterpene synthase gene, designated as GmOCS, was identified to be responsible for the biosynthesis of (E)-ß-ocimene through genome-wide gene family screening and in vitro and in vivo assays. Results from transgenic soybean and tobacco confirmed that (E)-ß-ocimene catalyzed by GmOCS had pivotal roles in repelling a S. litura attack. This study advances the understanding of (E)-ß-ocimene synthesis and its function in crops, as well as provides a good candidate for further anti-insect soybean improvement.

Allelic variation of terpene synthases drives terpene diversity in the wild species of the Freesia genus.

Terpene synthases (TPSs) play pivotal roles in conferring the structural diversity of terpenoids, which are mainly emitted from flowers, whereas the genetic basis of the release of floral volatile terpenes remains largely elusive. Though quite similar in sequence, TPS allelic variants still function divergently, and how they drive floral terpene diversity in closely related species remains unknown. Here, TPSs responsible for the floral scent of wild Freesia species were characterized, and the functions of their natural allelic variants, as well as the causal amino acid residues, were investigated in depth. Besides the 8 TPSs previously reported in modern cultivars, 7 additional TPSs were functionally evaluated to contribute to the major volatiles emitted from wild Freesia species. Functional characterization of allelic natural variants demonstrated that allelic TPS2 and TPS10 variants changed the enzymatic capacity while allelic TPS6 variants drove the diversity of floral terpene products. Further residue substitution analysis revealed the minor residues determining the enzyme catalytic activity and product specificity. The clarification of TPSs in wild Freesia species reveals that allelic TPS variants evolved differently to determine the interspecific floral volatile terpenes in the genus and might be used for modern cultivar improvement.

Electrochemical properties and facile preparation of hollow porous V2O5 microspheres for lithium-ion batteries.

Vanadium pentoxide (V2O5) has shown great potential to be used in lithium-ion batteries (LIBs), but it has limited applications because it has cycle instability and poor rate capability, and its lithiation mechanism is not well understood. In this work, hollow porous V2O5 microspheres (HPVOM) were obtained by a facile poly(vinylpyrrolidone) and ethylene glycol-assisted soft-template solvothermal method. Half cells with HPVOM exhibited good capacity, rate capability, and stability, delivering 407.9 mAh g-1 at 1.0 A g-1 after 700 cycles. Furthermore, a LiFePO4/HPVOM full cell had a discharge capacity of 109.9 mAh g-1 after 150 cycles at 0.1 A g-1. Using an equivalent circuit model (ECM) and distribution of relaxation times (DRT), we found that the charge-transfer (including the solid-state interface resistance) and bulk resistances varied regularly with the charge/discharge state, while the electrolyte resistance was largely maintained. The bulk resistance finally vanished, indicative of dynamic activation. The method used to prepare the hollow microspheres, as well as the display of electrode kinetics via ECM and DRT, could be broadly applied in developing efficient electrodes for LIBs.

A Reconfigurable Optoelectronic Synaptic Transistor with Stable Zr-CsPbI3 Nanocrystals for Visuomorphic Computing.

Reconfigurable phototransistor memory attracts considerable attention for adaptive visuomorphic computing, with highly efficient sensing, memory, and processing functions integrated onto a single device. However, developing reconfigurable phototransistor memory remains a challenge due to the lack of an all-optically controlled transition between short-term plasticity (STP) and long-term plasticity (LTP). Herein, an air-stable Zr-CsPbI3 perovskite nanocrystal (PNC)-based phototransistor memory is designed, which is capable of broadband photoresponses. Benefitting from the different electron capture ability of Zr-CsPbI3 PNCs to 650 and 405 nm light, an artificial synapse and non-volatile memory can be created on-demand and quickly reconfigured within a single device for specific purposes. Owing to the optically reconfigurable and wavelength-aware operation between STP and LTP modes, the integrated blue feature extraction and target recognition can be demonstrated in a homogeneous neuromorphic vision sensor array. This work suggests a new way in developing perovskite optoelectronic transistors for highly efficient in-sensor computing.

The biochemical and molecular investigation of flower color and scent sheds lights on further genetic modification of ornamental traits in Clivia miniata.

Clivia miniata is renowned for its evergreen and strap-like leaves, whereas its floral color and scent are lacking diversity. Here, anthocyanin, volatile terpene, and carotenoid metabolisms were integrally investigated in C. miniata flowers. The results showed that pelargonidins and lutein might cooperate to confer orange or yellow color to C. miniata flowers, but only a trace amount of (+)-limonene was detected. The expression levels of CmF3'H and CmDFR appeared to be responsible for the ratio of cyanidin and pelargonidin derivatives in C. miniata, and the low expression of CmF3'H was responsible for the lack of cyanidins in flowers. Moreover, the CmF3'H promoter could not be activated by CmMYBAs, suggesting that it was controlled by novel regulators. Only two CmTPSs were functional, with CmTPS2 responsible for (+)-limonene synthesis, contributing to the monotonous flower volatile terpenes of C. miniata. CmCCD1a and CmCCD1b were able to cleave carotenoids at the 5,6 (5',6'), and 9,10 (9',10') positions to generate volatile apocarotenoids, whereas the substrates found in low-quantities or specific subcellular localizations of CmCCD1s might constrain volatile apocarotenoid release. Consequently, activating F3'H and introducing novel F3'5'H or versatile TPS may be effective ways to modify the floral color and scent, respectively. Alternatively, modifying the carotenoid flux or CCD1 localization might affect floral color and scent simultaneously. Taking these results together, the present study provides a preliminary deciphering of the genetic constraints underlying flower color and scent development, and proposes possible schemes for further genetic modification of ornamental traits in C. miniata and other plants.

Exploring the ozone pollution over the western Sichuan Basin, Southwest China: The impact of diurnal change in mountain-plains solenoid.

The Sichuan Basin (SCB), to the east of the Tibetan Plateau (TP), experiences severe ozone (O3) pollution. Unfavorable atmospheric diffusion conditions are considered the main causes of heavy air pollution over the basin. However, the meteorological impact of thermally driven mountain-plains solenoid (MPS) between the TP and SCB on O3 pollution has not been reported. Here we show the MPS driving the diurnal O3 changes in the atmospheric boundary layer over the SCB based on surface and high-resolution vertical observations, ERA5 reanalysis data, and the WRF-Chem model. The MPS shifts between upslope and easterly flows along the eastern slope of the TP and SCB during the day and downslope westerly flows to the western SCB at night. The daytime MPS flows drive the westward transport of O3-rich air mass in the atmospheric boundary layer from the polluted SCB and accumulate high O3 levels from the western edge of the SCB to the eastern slope of TP, subsequently aggravating O3 pollution in this region. After sunset, the MPS drainage flows carry air containing elevated O3 eastward downslope along the eastern slope of the TP into the nocturnal residual layer, enhancing the O3 concentrations aloft over the western SCB. The high-level O3 in the residual layer is transported downstream by nocturnal prevailing winds and contributes significantly to the next-day surface O3 buildup in the downwind region through daytime vertical mixing (~30 µg m-3 h-1). The present study reveals a transport mechanism driven by the MPS with coupling diurnal changes in the atmospheric boundary layer, which redistributes O3 over the basin and exacerbates O3 pollution along the western edge of the basin. This study has important implications for understanding meteorological drivers on atmospheric environment underlying the complex terrain.

Nonflammable, robust and flexible electrolytes enabled by phosphate coupled polymer-polymer for Li-metal batteries.

Liquid organic electrolytes commonly employed in commercial Li-ion batteries suffer from safety issues such as flammability and explosions. Replacing liquid electrolytes with nonflammable electrolytes has become increasingly attractive in the development of safe, high-energy Li-metal batteries (LMBs). In this work, nonflammable, robust, and flexible composite polymer-polymer electrolytes (PPEs) were successfully fabricated by flame-retardant solution casting with polyimide (PI) and polyvinylidene fluoride (PVDF). The optimized nonflammable PPEs (e.g., PPE-50) demonstrate not only good mechanical properties (i.e., a high tensile strength of 29.6 MPa with an elongation at break of 87.2%), but also high Li salts dissolubility, the former of which ensures the suppression of Li dendrites, while the latter further improves the ionic conductivity (∼1.86 × 10-4 S cm-1 at 30 °C). The resulting symmetric cells (Li|PPE-50|Li) offer excellent Li stripping and plating stability for 1000 h at 0.5 mA cm-2/0.25 mAh cm-2 and 600 h at 2.0 mA cm-2/1.0 mAh cm-2. In addition, the LiFePO4|PPE-50|Li half cells show high cycling performance (e.g., a reversible discharge capacity of 135.9 mAh g-1 after 300 cycles at 1C) and rate capability (e.g., 117.2 mAh g-1 at 4C). The PPE-50 is also compatible with a high-voltage cathode (e.g., LiNi0.5Mn0.3Co0.2O2), and the resulting batteries demonstrate long-term cycling stability with a high cut-off voltage of 4.5 V vs. Li/Li+. Because of the incorporation of a mechanically robust and thermally stable PI, a polar PVDF, and flame-retardant trimethyl phosphate (TMP) within PPEs, as well as the coordination between Li salts and TMP, and the interaction between Li salts and polymers (especially between Li bis(oxalato)borate) and PI, as well as the bis(oxalato)borate anion and PI), PPEs show great potential for practical and high-energy LMBs without safety concerns.

Novel Water-Soluble Chlorin-Based Photosensitizer for Low-Fluence Photodynamic Therapy.

Photodynamic therapy (PDT), performed with low-fluence rates, can improve antitumor responses and prevent adverse effects. However, photosensitizers (PSs) for low-fluence PDT treatment are rarely reported. Herein, we exploited an amphiphilic chlorin-based PS, named DYSP-C34, which has a variety of beneficial biological properties, such as improved water solubility, better cellular permeability, specific localization and enhanced phototoxicity under low light dose irradiation. In addition, DYSP-C34 could effectively accumulate in a mouse subcutaneous xenograft tumor and exhibit substantial tumor regression after irradiation with an extremely low light fluence (6 J/cm2). Meanwhile, the excellent phototoxicity could stimulate the host immune system and lead to a strong inhibition of tumor growth synergistically. These results indicated the potential value of DYSP-C34 as a chlorin-type PS for low-fluence PDT application.

Characterization of Terpene synthase variation in flowers of wild aquilegia species from Northeastern Asia.

There are several causes for the great diversity in floral terpenes. The terpene products are determined by the catalytic fidelity, efficiency and plasticity of the active sites of terpene synthases (TPSs). However, the molecular mechanism of TPS in catalyzing terpene biosynthesis and its evolutionary fate in wild plant species remain largely unknown. In this study, the functionality of terpene synthases and their natural variants were assessed in two Northeastern Asia endemic columbine species and their natural hybrid. Synoptically, TPS7, TPS8, and TPS9 were highly expressed in these Aquilegia species from the Zuojia population. The in vitro and in vivo enzymatic assays revealed that TPS7 and TPS8 mainly produced (+)-limonene and ß-sesquiphellandrene, respectively, whereas TPS9 produced pinene, similar to the major components released from Aquilegia flowers. Multiple sequence alignment of Aquilegia TPS7 and TPS8 in the Zuojia population revealed amino acid polymorphisms. Domain swapping and amino acid substitution assays demonstrated that 413A, 503I and 529D had impacts on TPS7 catalytic activity, whereas 420G, 538F and 545 L affected the ratio of ß-sesquiphellandrene to ß-bisabolene in TPS8. Moreover, these key polymorphic amino acid residues were found in Aquilegia species from the Changbai Mountain population. Interestingly, amino acid polymorphisms in TPSs were present in individuals with low expression levels, and nonsynonymous mutations could impact the catalytic activity or product specificity of these genes. The results of this study will shed new light on the function and evolution of TPS genes in wild plant species and are beneficial to the modification of plant fragrances.

CircSAMD11 facilitates progression of cervical cancer via regulating miR-503/SOX4 axis through Wnt/ß-catenin pathway.

Cervical cancer (CC) is a common gynaecological malignant tumour with a high mortality rate. Circular RNAs (circRNAs) play a critical role in tumour occurrence and development. This study aimed to investigate the function and molecular basis of hsa_circ_0009189 (circSAMD11) in CC development. RNA levels were determined by qRT-PCR, and protein expression was measured by western blot. Cell proliferation, migration, invasion and apoptosis were detected by Cell Counting Kit-8 (CCK-8), colony formation, Transwell and flow cytometry assays. The relationship between miR-503 and circSAMD11/SOX4 was validated via dual-luciferase reporter assay, RIP or RNA pull-down assay. Xenograft assay was conducted to test tumour growth in vivo. CircSAMD11 and SOX4 levels were elevated, while miR-503 level was reduced in CC tissues and cells. Knockdown of circSAMD11 suppressed CC cell proliferation, migration and invasion and accelerated apoptosis. CircSAMD11 was localised in cytoplasm and directly targeted miR-503. Also, circSAMD11 sponged miR-503 to modulate SOX4 expression. Additionally, circSAMD11 regulated CC progression via absorbing miR-503 or modulating SOX4. Besides, depletion of circSAMD11 hindered tumorigenesis in vivo. CircSAMD11 contributed to CC progression by regulating miR-503/SOX4 signalling and activating Wnt/ß-catenin pathway, which provides a promising therapeutic target for cervical cancer.

[Pharmacokinetics and tissue distribution characteristics of the novel photosensitizer 32-(4-methoxyphenyl)-152-aspartyl-chlorin e6].

Photodynamic therapy (PDT) has garnered immense research interest. PDT can directly kill the cells via a combination of photosensitizer, light, and molecular oxygen. It has emerged as a promising therapeutic option for cancer treatment owing to its advantages such as minimized systemic toxicity, minimal invasiveness, high therapeutic efficacy, and potential for developing antitumor immunity. The novel photosensitizer 32-(4-methoxyphenyl)-152-aspartyl-chlorin e6 (DYSP-C34) was synthesized by introducing a 32-aryl substitution and amino acid substituent of the Chenghai chlorin (CHC). Briefly, 32-(4-methoxyphenyl) substitution was achieved via olefin metathesis reactions. The aspartic acid side chain was introduced regioselectively at C-152, followed by hydrolysis to yield the target DYSP-C34. CHC with the same chemical structure as chlorin e6 was prepared from chlorophyll a, which was extracted from Spirulina powders derived from Chenghai Lake in the Yunnan province of China. This strategy successfully endowed the resultant photosensitizer with better cellular permeability and increased water solubility. In addition, the photodynamic antitumor effects of PDT largely depend on the dose of photosensitizer used, time between photosensitizer administration and light exposure, and possibly other still poorly known variables. Determination of optimal conditions for PDT requires a coordinated interdisciplinary effort. Therefore, the pharmacokinetics and tissue distribution of DYSP-C34 in vivo are critical for the efficacy and safety of PDT. Herein, a high performance liquid chromatography-ultraviolet (HPLC-UV) detection method was established for the determination of the new photosensitizer DYSP-C34 in rat plasma. The sample preparation involved a protein-precipitation and liquid-liquid extraction method. Methanol was used to precipitate proteins and chloroform was used to extract chlorins. Then, DYSP-C34 was separated on a Unitary C18 column (250 mm×4.6 mm, 5 µm) with a mobile phase comprising methanol and 5 mmol/L tetrabutylammonium phosphate buffer solution (70∶30, v/v). The flow rate was 1.0 mL/min with UV detection using a wavelength of 400 nm at 40 ℃. Results showed that DYSP-C34 and chlorin e6 trimethyl ester (IS) were well separated under these conditions. The method was sensitive and sufficiently precise with a good linear relationship (determination coefficient (r2)=0.9941) over the range of 1-200 µg/mL in rat plasma. At three spiked levels (8, 40, and 120 µg/mL), the average recoveries were 74.39%, 69.71%, and 65.89%, respectively. The intra-day and inter-day relative standard deviations (RSDs) were lower than 5%. The precision met the requirements of biological sample determination. Furthermore, DYSP-C34 was stable in rat plasma under various storage conditions at room temperature, three freeze-thaw cycles, and long-term cryopreservation. The validated method was successfully applied to the pharmacokinetic study of DYSP-C34 after intravenous injection of a single dose in rat plasma. The pharmacokinetic parameters after intravenous injection of DYSP-C34 (16 mg/kg) were calculated. The plasma half-life (t1/2z) was 6.98 h, the area under the plasma concentration-time curve AUC(0-∞) was 1025.01 h·mg/L and the mean retention time MRT(0-∞) was 9.19 h. In addition, the results of DYSP-C34 distribution in tumor-bearing mice showed that DYSP-C34 could accumulate in tumor tissues, with higher concentrations in liver and kidney tissues, and lower concentrations in heart, spleen, and lung tissues. In summary, a specific, simple, and accurate HPLC-UV method was developed and validated for the determination of DYSP-C34 in rat plasma and tumor-bearing mouse tissues. The pharmacokinetics of DYSP-C34 after intravenous administration in rats and the tissue distribution characteristics of tumor-bearing mice were clarified for the first time. It is significant for clinical rational drug use and pharmacodynamic research. Therefore, choosing an appropriate time for light treatment time can achieve the best photodynamic effect. The results of pharmacokinetics and tissue distribution of DYSP-C34 provide vital guidance for subsequent pharmacodynamic research and further clinical trials in terms of dosage, light time, light toxicity and side effects.

An ultrasound-driven immune-boosting molecular machine for systemic tumor suppression.

Exploring facile and effective therapeutic modalities for synergistically controlling primary tumor and metastasis remains a pressing clinical need. Sonodynamic therapy (SDT) offers the possibility of noninvasively eradicating local solid tumors, but lacks antimetastatic activity because of its limited ability in generating systemic antitumor effect. Here, we exploited a previously unidentified ultrasound-driven "molecular machine," DYSP-C34 (C34 for short), with multiple attractive features, emerging from preferential tumor accumulation, potent ultrasound-triggered cytotoxicity, and intrinsic immune-boosting capacity. Driven by the ultrasound, C34 functioned not only as a tumor cell killing reagent but also as an immune booster that could potentiate robust adaptive antitumor immunity by directly stimulating dendritic cells, resulting in the eradication of the primary solid tumor along with the inhibition of metastasis. This molecular machine, C34, rendered great promise to achieve systemic treatment against cancer via unimolecule-mediated SDT.

Total synthesis and biological evaluation of 7-hydroxyneolamellarin A as hypoxia-inducible factor-1α inhibitor for cancer therapy.

7-Hydroxyneolamellarin A (7-OH-Neo A, 1), a natural marine product derived from sponge Dendrilla nigra, was first synthesized with 10% overall yield under the instruction of convergent synthetic strategy. We found that 7-OH-Neo A could attenuate the accumulation of hypoxia-inducible factor-1α (HIF-1α) protein and inhibit vascular epidermal growth factor (VEGF) transcriptional activity, showing well inhibitory effect on HIF-1 signaling pathway. Meantime, 7-OH-Neo A had the well anti-tumor activities, such as inhibiting tumor angiogenesis, proliferation, migration and invasion. More importantly, 7-OH-Neo A exhibited profound anti-tumor effect in mice breast cancer model by suppressing the accumulation of HIF-1α in tumor tissue. Mechanism study demonstrated that 7-OH-Neo A might target the protein with the ability of stabilizing HIF-1α in hypoxia. Due to the excellent water solubility, superior anti-tumor activity and good biocompatibility, 7-OH-Neo A shows the promising potential for being exploited as an anti-tumor agent in near future.

Synthesis and biological evaluation of NO-donor containing photosensitizers to induce ferroptosis of cancer cells.

Photodynamic therapy (PDT) is a non-invasive treatment method for tumors by exciting photosensitizers (PS) upon light irradiation to generate cytotoxic reactive oxygen species (ROS). However, the low oxygen concentration near the tumor tissue limits the therapeutic effect of PDT. Herein, we synthesized six chlorin e6 derivatives containing NO-donors to enhance their antitumor activity by synergistic effect of ROS and NO. The results revealed that the new NO-donor containing photosensitizers (PS-NO) exhibited more potent photodynamic activity than chlorin e6, and the introduction of NO donor moieties to chlorin e6 increased the level of NO and ROS in cells. The addition of Ferrostatin-1, a ferroptosis inhibitor, markedly reduced the photodynamic activity of PS-NO as well as the level of NO and ROS in cells. Mechanism studies further showed that PS-NO could reduce intracellular GSH level, inhibit GPX4 activity and promote malondialdehyde (MDA) accumulation upon light irradiation, which suggested the ferroptosis mechanism underlying the PDT effect of PS-NO.