Lipid-Polymer Nanoparticles Mediate Compartmentalized Delivery of Cas9 and sgRNA for Glioblastoma Vasculature and Immune Reprogramming.

Hypervascularized glioblastoma is naturally sensitive to anti-angiogenesis but suffers from low efficacy of transient vasculature normalization. In this study, a lipid-polymer nanoparticle is synthesized to execute compartmentalized Cas9 and sgRNA delivery for a permanent vasculature editing strategy by knocking out the signal transducer and activator of transcription 3 (STAT3). The phenylboronic acid branched cationic polymer is designed to condense sgRNA electrostatically (inner compartment) and patch Cas9 coordinatively (outer compartment), followed by liposomal hybridization with angiopep-2 decoration for blood-brain barrier (BBB) penetration. The lipid-polymer nanoparticles can reach glioblastoma within 2 h post intravenous administration, and hypoxia in tumor cells triggers charge-elimination and degradation of the cationic polymer for burst release of Cas9 and sgRNA, accompanied by instant Cas9 RNP assembly, yielding ≈50% STAT3 knockout. The downregulation of downstream vascular endothelial growth factor (VEGF) reprograms vasculature normalization to improve immune infiltration, collaborating with interleukin-6 (IL-6) and interleukin-10 (IL-10) reduction to develop anti-glioblastoma responses. Collectively, the combinational assembly for compartmentalized Cas9/sgRNA delivery provides a potential solution in glioblastoma therapy.

Ball-in-ball NiS2@CoS2 heterojunction driven by Kirkendall effect for high-performance Mg2+/Li+ hybrid batteries.

Mg2+/Li+ hybrid batteries (MLHBs), which support the rapid insertion and removal of Mg2+/Li+ bimetallic ions, are promising energy storage systems. Inspired by the Kirkendall effect, ball-in-ball bimetallic sulfides with heterostructures were prepared as cathode materials for the MLHBs. First, a nickel-cobalt precursor (NiCo-X precursor) with three-dimensional (3D) nanosheets on its surface was prepared using a solvothermal method based on the association reaction between alkoxide molecules. Subsequently, the NiCo-X precursor was vulcanized at high temperature using the potential energy difference as the driving force to successfully prepare NiS2@CoS2 core-shell hollow spheres. When used as the positive electrode material for the MLHBs, the NiS2@CoS2 hollow spheres exhibited excellent Mg2+/Li+ ion storage capacity, high specific capacity, good rate performance, and stable cyclic stability owing to their tough hierarchical structure. At a current density of 500 mA g-1, a specific capacity of 536 mAh g-1 was maintained after 200 cycles. By explaining the transformation mechanism of Mg2+/Li+ in bimetallic sulfides, it was proven that Mg2+ and Li+ worked cooperatively. This study provides a new approach for developing MLHBs with good electrochemical properties.

Enzyme-Silenced Nanosponges Prolong Intratumoral Lifetime to Facilitate Intercellular Relay Drug Delivery and Treatment Efficacy.

The clinical application of nanomedicines faces the dilemma of improved safety but restricted efficacy due to the poor intratumoral bioavailability of chemotherapeutics. We here design an enzyme-silenced nanosponge that shares a long-term lifespan to reversibly exhale/inhale doxorubicin (DOX) for continuous intercellular relay delivery and improved intratumoral retention. The nanosponge is composed of a cationic lipid overlaying a hyaluronic acid derivative polyampholyte core for enveloping of DOX and hyaluronidase-1-targeted siRNA (siHyal1), and a lipoprotein shell decorated with fusion peptide 4F-tLyP-1 that was fused with apolipoprotein A-I (apoA-I) mimetic peptide 4F and tLyP-1 for tumor homing and extravasation into the tumor interstitium. Triggered by the intra/intercellular pH variation, the nanosponge core could reversibly swell in endo/lysosome (pH 5.0) for DOX release. Owing to the deprotonation, the nanosponge core shrinks back in cytoplasm (pH 7.4) for DOX reloading and continues the behavior after being secreted to the extracellular matrix (pH 6.8) via Golgi apparatus, which dramatically improves intratumoral DOX retention and availability. Concurrently, the intratumoral lifespan of the nanosponge is prolonged by siHyal1-specific silencing, ensuring spatiotemporal consistency of carrier and drug when shuttling multilayer tumor cells. As a result, the nanosponge achieves efficient tumor inhibition in 99.1% of tumor spheroids and 80.1% of orthotopic tumor models. Collectively, this study provides an intelligent nanosponge design for active intercellular relay drug delivery, achieving improved intratumoral bioavailability of drugs and amplified chemotherapy on solid tumors.

A Nanodisc-Paved Biobridge Facilitates Stem Cell Membrane Fusogenicity for Intracerebral Shuttling and Bystander Effects.

Mesenchymal stem cell (MSC) therapies experience steadfast clinical advances but are still hindered by inefficient site-specific migration. An adaptable MSC membrane fusogenicity technology is conceptualized for lipid raft-mediated targeting ligand embedding by using toolkits of discoidal high-density lipoprotein (HDL)-containing biomimicking 4F peptides. According to the pathological clues of brain diseases, the vascular cell adhesion molecule 1 specialized VBP peptide is fused with 4F to assemble 4F-VBP (HDL), which acts as a biobridge and transfers VBP onto the living cell membrane via lipid rafts for surface engineering of MSCs in suspension. When compared with the membrane-modifying strategies of PEGylated phospholipids, 4F-VBP (HDL) provides a 3.86 higher linkage efficiency to obtain MSCs4F-VBP(HDL) , which can recognize and adhere to the inflammatory endothelium for efficient blood-brain barrier crossing and brain accumulation. In APPswe/PSEN1dE9 mice with Alzheimer's disease (AD), the transcriptomic analysis reveals that systemic administration of MSCs4F-VBP(HDL) can activate pathways associated with neuronal activity and diminish neuroinflammation for rewiring AD brains. This customizable HDL-mediated membrane fusogenicity platform primes MSC inflammatory brain delivery, which can be expanded to other disease treatments by simply fusing 4F with relevant ligands for living cell engineering.

20(S)-ginsenoside Rh1 alleviates T2DM induced liver injury via the Akt/FOXO1 pathway.

Diabetes-associated liver injury becomes a dominant hepatopathy, leading to hepatic failure worldwide. The current study was designed to evaluate the ameliorative effects of ginsenoside Rh1 (G-Rh1) on liver injury induced by T2DM. A T2DM model was established using C57BL/6 mice through feeding with HFD followed by injection with streptozotocin at 100 mg·kg-1.. Then the mice were continuously administered with G-Rh1 (5 and 10 mg·kg-1), to explore the protective effects of G-Rh1 against liver injury. Results showed that G-Rh1 exerted significant effects on maintaining the levels of FBG and insulin, and ameliorated the increased levels of TG, TC and LDL-C induced by T2DM. Moreover, apoptosis in liver tissue was relieved by G-Rh1, according to histological analysis. Particularly, in diabetic mice, it was observed that not only the increased secretion of G6Pase and PEPCK in the gluconeogenesis pathway, but also inflammatory factors including NF-κB and NLRP3 were suppressed by G-Rh1 treatment. Furthermore, the underlying mechanisms by which G-Rh1 exhibited ameliorative effects was associated with its capacity to inhibit the activation of the Akt/FoxO1 signaling pathway induced by T2DM. Taken together, our preliminary study demonstrated the potential mechnism of G-Rh1 in protecting the liver against T2DM-induced damage.

When Natural Compounds Meet Nanotechnology: Nature-Inspired Nanomedicines for Cancer Immunotherapy.

Recent significant strides of natural compounds in immunomodulation have highlighted their great potential against cancer. Despite many attempts being made for cancer immunotherapy, the biomedical application of natural compounds encounters a bottleneck because of their unclear mechanisms, low solubility and bioavailability, and limited efficacy. Herein, we summarize the immune regulatory mechanisms of different natural compounds at each step of the cancer-immunity cycle and highlight their anti-tumor potential and current limitations. We then propose and present various drug delivery strategies based on nanotechnology, including traditional nanoparticles (NPs)-based delivery strategies (lipid-based NPs, micelles, and polysaccharide/peptide/protein-based NPs) and novel delivery strategies (cell-derived NPs and carrier-free NPs), thus providing solutions to break through existing bottlenecks. Furthermore, representative applications of nature-inspired nanomedicines are also emphasized in detail with the advantages and disadvantages discussed. Finally, the challenges and prospects of natural compounds for cancer immunotherapy are provided, hopefully, to facilitate their far-reaching development toward clinical translation.

The regular pattern of metabolite changes in mushroom Inonotus hispidus in different growth periods and exploration of their indicator compounds.

Inonotus hispidus is a valuable and rare edible and medicinal mushroom with extremely high nutritional and medicinal value. However, there is no holistic insight to elucidate the molecular basis of the differentiated usage and accurate annotation of physiological maturity to fluctuating yields and quality. This study aimed to figure out the fruiting bodies' metabolites change regulation and potential maturating indicators to distinguish different quality I. hispidus. We applied non-targeted ultra-high performance liquid chromatography and high-resolution mass spectrometry combined and with multivariate analysis and analyzed cultivated and wild mushroom I. hispidus in different growth periods (budding, mature and aging). With the fruiting bodies maturating, 1358 metabolites were annotated, 822 and 833 metabolites abundances changed greater than or equal to 1 time from the budding period to the aging period in abundance in cultivated and wild, the total polysaccharides, crude fat, total flavonoids, and total terpenes increased at first and then decreased. Total amino acids, crude protein, and total polyphenols decreased, while the total steroids increased linearly. The change of metabolites showed certain regularity. Metabolic pathways enrichment analysis showed that these metabolites are involved in glycolysis, biosynthesis of amino acids, organic acid metabolism, glycine-serine-and-threonine metabolism, tricarboxylic acid cycle, purine metabolism, and pyrimidine metabolism. In addition, ergosterol peroxide and (22E)-ergosta-4,6,8(14),22-tetraen-3-one can be used as indicator compounds, and their contents increase linearly with the fruiting bodies of I. hispidus' physiological maturation. This comprehensive analysis will help to evaluate the edible values and facilitate exploitation in mushroom I. hispidus.

Lipoprotein-Inspired Nanoscavenger for the Three-Pronged Modulation of Microglia-Derived Neuroinflammation in Alzheimer's Disease Therapy.

The inflammatory dysfunction of microglia from excess amyloid-ß peptide (Aß) disposal is an overlooked but pathogenic event in Alzheimer's disease (AD). Here, we exploit a native high-density lipoprotein (HDL)-inspired nanoscavenger (pHDL/Cur-siBACE1) that combines the trinity of phosphatidic acid-functionalized HDL (pHDL), curcumin (Cur), and ß-site APP cleavage enzyme 1 targeted siRNA (siBACE1) to modulate microglial dysfunction. By mimicking the natural lipoprotein transport route, pHDL can penetrate the blood-brain barrier and sequentially target Aß plaque, where Aß catabolism is accelerated without microglial dysfunction. The benefit results are from a three-pronged modulation strategy, including promoted Aß clearance with an antibody-like Aß binding affinity, normalized microglial dysfunction by blocking the NF-κB pathway, and reduced Aß production by gene silence (44%). After treatment, the memory deficit and neuroinflammation of APPswe/PSEN 1dE9 mice are reversed. Collectively, this study highlights the double-edged sword role of microglia and provides a promising tactic for modulating microglial dysfunction in AD treatment.

Versatile nanomaterials for Alzheimer's disease: Pathogenesis inspired disease-modifying therapy.

Current therapeutic strategies for Alzheimer's disease (AD) face the dilemma of no effective drugs that can delay the onset or slow the disease progression. Despite tremendous effort being involved, several anti-AD drugs come into clinical trials but with a moderate-to-poor success rate due to the complex AD pathogenesis and the blood-brain barrier (BBB). Insight into the complex AD pathogenesis is enabling new inspiration that have the potential to help improve our understanding and design of anti-AD nanomedicine. Herein, the complex AD pathogenesis and interaction between different therapeutic targets are summarized and highlighted, and key challenges facing translation of anti-AD nanomedicine from benchtop to bedside are discussed. Following combing through the complex pathogenesis and a contextual overview of clinical status of anti-AD compounds, we discuss the recent advances of exploring versatile nanomaterials in AD treatment from the pathogenesis. The focus here is especially on how to design pathogenesis-inspired nanomaterials for delivering therapeutics cross BBB and modulating the AD pathology by themselves as active ingredients. Collectively, this review highlights the pathogenesis-oriented nanomedicine design and provides with an easily accessible guide to the key opportunities and challenges currently facing the anti-AD nanomedicine.

A conservation planning framework for China's national key ecological function area based on ecological risk assessment.

National Key Ecological Functions Areas (NKEFAs) in China perform critical ecological functions and play a key role in ensuring the ecological safety of a large region or the whole country. Conservation planning in NKEFAs needs to scientifically locate conservation areas and development sites to support the "globally conserved, locally developed" strategy. However, popular conservation planning approaches often underestimate the impacts of natural and anthropogenic stressors and thus fail to handle the conflicts between conservation and development goals. This article proposes a conservation planning framework (CP-NKEFA) to overcome the limitations of popular conservation planning approaches and fulfill the conservation planning requirements of China's NKEFAs. Conservation planning is converted to an ecological risk assessment problem to integrate natural and anthropogenic stressors analysis with ecosystem service (ES) evaluation. The framework clarifies stressor types and quantifies stressor risks and ES importance to set conservation, development, and buffer zones. As a case study, the framework was implemented in Changyang County, China, an NKEFA for water and soil retention in the Three Gorges Reservoir Region. The framework is more useful than typical ecological redline zoning for instructing conservation and development spatial arrangement with a multi-category zoning scheme. The zoning results protect the areas vulnerable to natural and anthropogenic stressors or significant for ES provisions. Furthermore, the buffer zone prevents direct impacts of human activities on conservation areas and permits trade-offs between conservation and development goals. Except for NKEFAs, the framework also applies to conservation planning in other areas where conservation and development goals must be handled.

[Analysis of material basis of Schisandrae Chinensis Fructus in different growth stages based on chromatography].

Schisandrae Chinensis Fructus in six growth stages was taken as materials to study the species and content changes of material basis, which were detected by UPLC, GC and MS chromatography, including lignans, nucleosides, aroma components and fatty acids. The results showed that the texture, color and taste of Schisandrae Chinensis Fructus in six growth stages were different. On the material basis, 12 lignans were detected by UPLC-MS, and the content of total lignans was higher in the samples from late August to early September, among which the highest content of schisandrin was 0.67%±0.01%, followed by schizandrol B, angeloylgomisin H and schisandrin B, and the total content increased with the maturity of Schisandrae Chinensis Fructus. Thirteen kinds of nucleosides were detected by UPLC. The total nucleoside content was the highest in late July samples, in which the contents of uridine and guanosine were higher and decreased after maturity. Aroma components and fatty acids were identified by GC-MS. A total of 53 aroma components were detected and the highest total content was appeared in late August samples, of which ylangene was higher and bergamotene was followed. A total of 24 kinds of fatty acids were detected. The fruits matured basically in August, and the content of fatty acids in the samples was the highest, among which linoleic acid content was top the list and oleic acid was the second. To sum up, the maturity of Schisandra chinensis fruit is related to the content and variety of various material bases, and the growth period has different influences on the quality of Schisandrae Chinensis Fructus. Therefore, the appropriate harvesting time should be determined according to the change law of target components. The results of this study can provide reference for the quality evaluation of Schisandrae Chinensis Fructus material basis.

Pulchinenoside B4 exerts the protective effects against cisplatin-induced nephrotoxicity through NF-κB and MAPK mediated apoptosis signaling pathways in mice.

Cisplatin (cis-Dichlorodiammine platinum, CP), as the first-line chemotherapy drug of choice for many cancers such as urogenital system tumors and digestive tract tumors, also causes toxicity and side effects to the kidney. Previous studies have shown that Pulsatilla chinensis has significant anti-inflammatory and antioxidant activities, but the mechanism of cisplatin induced acute kidney injury (AKI) in vivo has not been thoroughly studied. The purpose of this study is to investigate the protective effect of pulchinenoside B4 (PB4), a representative and major component with a content of up to 10% in root of P. chinensis, on AKI induced by CP in mice. Our results indicated the significant protective effect of PB4 by evaluating renal function indicators, inflammatory factor levels and renal histopathological changes. In addition, PB4 may mainly act on NF-κB signaling pathway to reduce the levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1ß), cyclooxygenase-2 (COX-2), and inducible nitric oxide synthase (iNOS) in the kidney after CP exposure, thus exerting anti-inflammatory activity. Furthermore, PB4 regulated MAPK signaling pathway and its downstream apoptotic factors to inhibit the occurrence of apoptosis, such as Bax, Bcl-2, caspase 3 and caspase 9. Notably, the activations of caspase 3 induced by cisplatin were strikingly reduced in PB4-treated mice. Therefore, the above evidence suggested that PB4 is a potential renal protectant with significant anti-inflammatory and anti-apoptotic effects.

Amino acid, fatty acid, and carbohydrate metabolomic profiles with ginsenoside-induced insecticidal efficacy against Ostrinia furnacalis (Guenee).

BACKGROUND: Previous studies have shown the insecticidal efficacy of ginsenosides. In the present study, we aimed to investigate the metabolic mechanism related to the inhibitory effect of panaxadiol saponins (PDSs) against the Asian corn borer Ostrinia furnacalis (Guenee). METHODS: Third instar larvae of O. furnacalis were fed normal diets with different concentrations of PDSs for 4 days. The consumption index, relative growth rate, approximate digestibility, and conversion of ingested and digested food were recorded. A targeted gas chromatography-mass spectrometry assay was performed to detect the profiles of amino acids, fatty acids, and carbohydrates in larvae of O. furnacalis. In addition, the activity of detoxification-related enzymes was determined. RESULTS AND CONCLUSIONS: PDSs decreased the consumption index, relative growth rate, approximate digestibility, and conversion of ingested and digested food in the 3rd instar larvae of O. furnacalis in a dose-dependent manner. PDSs decreased 15 free amino acids, 16 free fatty acids, and 5 carbohydrates and increased the levels of palmitoleic acid, palmitic acid, and 9-octadecenoic acid in the 3rd instar larvae. The activity of detoxification-related enzymes, such as acetylcholinesterase, glutathione S-transferase, cytochrome P450, carboxylesterase, trehalase, acid phosphatase, and alkaline phosphatase, was reduced in a dose-dependent manner in the 3rd instar larvae exposed to PDSs. These data confirmed the inhibitory effect of PDSs against growth, food utilization, and detoxification in the 3rd instar larvae of O. furnacalis and the potential for using PDSs as an efficient tool for insect pest management for O. furnacalis larvae.

FPOA induces the apoptosis of HepG2 cells.

The triterpenoid 3-acetoxylanosta-8,24-dien-21-oic acid (FPOA) is isolated from the fruiting body of Fomitopsis pinicola. The present study reports that FPOA exerts cytotoxic activity and describes the molecular mechanism of FPOA-induced apoptosis on human HepG2 hepatoma cells. FPOA exhibited significant cytotoxic effects against HepG2, MCF-7 and HeLa cells. However, FPOA was particularly cytotoxic towards HepG2 cells, with a half maximal inhibitory concentration value of 42.10 µM, thus these cells were taken forward for further analysis. Flow cytometry results demonstrated that FPOA significantly increased the apoptotic rate of HepG2 cells in a dose-dependent manner, explaining its potent cytotoxicity. In addition, western blot analysis revealed that FPOA significantly increased the B-cell lymphoma 2 (Bcl-2)-associated X/Bcl-2 ratio, and cytochrome c, caspase-9 and caspase-3 release, in addition to significantly decreasing poly(ADP) ribose polymerase levels. These observations indicate that FPOA induces the apoptosis of HepG2 cells by activating members of the caspase protein family and triggering the mitochondrial apoptosis signaling pathway. Based on these results, FPOA is a potential agent for the treatment of cancer.

Effects of processing method on the pharmacokinetics and tissue distribution of orally administered ginseng.

BACKGROUND: The use of different methods for the processing of ginseng can result in alterations in its medicinal properties and efficacy. White ginseng (WG), frozen ginseng (FG), and red ginseng (RG) are produced using different methods. WG, FG, and RG possess different pharmacological properties. METHODS: WG, FG, and RG extracts and pure ginsenosides were administered to rats to study the pharmacokinetics and tissue distribution characteristics of the following ginsenosides-Rg1, Re, Rb1, and Rd. The concentrations of the ginsenosides in the plasma and tissues were determined using UPLC-MS/MS. RESULTS: The rate and extent of absorption of Rg1, Re, Rb1, and Rd appeared to be affected by the different methods used in processing the ginseng samples. The areas under the plasma drug concentration-time curves (AUCs) of Rg1, Re, Rb1, and Rd were significantly higher than those of the pure ginsenosides. In addition, the AUCs of Rg1, Re, Rb1, and Rd were different for WG, FG, and RG. The amounts of Rg1, Re, Rd, and Rb1 were significantly (p < 0.05) higher in the tissues than those of the pure ginsenosides. The amounts of Re, Rb1, and Rd from the RG extract were significantly higher than those from the WG and FG extracts in the heart, lungs, and kidneys of the rats. CONCLUSION: Our results show that the use of different methods to process ginseng might affect the pharmacokinetics and oral bioavailability of ginseng as well as the tissue concentrations of Rg1, Re, Rd, and Rb1.

Facile Synthesis of π-Extended Viologens: Electron-Deficient Polycyclic Aza-aromatics.

A novel family of π-extended viologens has been synthesized by a concise 3-step route from simple and readily available chemicals. The π-enlargement gives the system new photophysical and electrochemical properties such as photoluminescence and changed redox potentials.

Governmental policies drive the LUCC trajectories in the Jianghan Plain.

The prosperity of farmers is closely tied to governmental policies. The Jianghan Plain is an important region for commodity grains, cotton and edible oil for China. The trajectories of land use and land cover change (LUCC) of the study area from 1995 to 2010 were studied based on the LUCC database of the Chinese Academy of Sciences. The LUCC was characterised by a continuous decrease of arable land and continuous increase of waters and construction land. The LUCC was obviously concurrent with the implementation of related national policies. The transition to construction land was ever well controlled by 'Notice regarding the further strengthening of land management and arable land protection' promulgated in 1997. However, it flourished again with the 'Rise of Central China Strategy' taking effect since 2006. The transition of construction land to others reflects an uncommon trend, which must be strengthened with the strict implementation of the overall plan, which imposes a limited acreage quota of construction land to each district. The policies were quite contradictory to the transition of waters. LUCC related to waters is most active, which was driven by both natural forces and national policies. Just after the devastating flood of 1998, the state council of China put forward the Green Policy to govern the major rivers. As to the study area, it is mainly to 'push over dykes to let flood through and return farmland to lakes'. In 2004, the Grain Direct Subsidy Policy was implemented, which, along with the surge in the price of rice, resulted in a strengthening trend of conversion of ponds to paddy fields.