Favorable efficacy and reduced acute neurotoxicity by antisense oligonucleotides with 2',4'-BNA/LNA with 9-(aminoethoxy)phenoxazine.

An increasing number of antisense oligonucleotides (ASOs) have been approved for clinical use. However, improvements of both efficacy and safety in the central nervous system (CNS) are crucial for the treatment with CNS diseases. We aimed to overcome the crucial issues by our development of various gapmer ASOs with a novel nucleoside derivative including a 2',4'-BNA/LNA with 9-(aminoethoxy)phenoxazine (BNAP-AEO). The various gapmer ASOs with BNAP-AEO were evaluated for thermal stability, in vitro and in vivo efficacy, and acute CNS toxicity. Thermal stability analysis of the duplexes with their complementary RNAs showed that ASOs with BNAP-AEO had a higher binding affinity than those without BNAP-AEO. In vitro assays, when transfected into neuroblastoma cell lines, demonstrated that ASOs with BNAP-AEO, had a more efficient gene silencing effect than those without BNAP-AEO. In vivo assays, involving intracerebroventricular injections into mice, revealed ASOs with BNAP-AEO potently suppressed gene expression in the brain. Surprisingly, the acute CNS toxicity in mice, as assessed through open field tests and scoring systems, was significantly lower for ASOs with BNAP-AEO than for those without BNAP-AEO. This study underscores the efficient gene-silencing effect and low acute CNS toxicity of ASOs incorporating BNAP-AEO, indicating the potential for future therapeutic applications.

Nonlinear Optical Saturable Absorption Properties of 2D VP Nanosheets and Application as SA in a Passively Q-Switched Nd:YVO4 Laser.

Two-dimensional (2D) violet phosphorus (VP) plays a significant role in the applications of photonic and optoelectronic devices due to its unique optical and electrical properties. The ultrafast carrier dynamics and nonlinear optical absorption properties were systematically investigated here. The intra- and inter-band ultrafast relaxation times of 2D VP nanosheets were measured to be ~6.83 ps and ~62.91 ps using the pump-probe method with a probe laser operating at 1.03 µm. The nonlinear absorption coefficient ßeff, the saturation intensity Is, the modulation depth ΔR, and the nonsaturable loss were determined to be -2.18 × 104 cm/MW, 329 kW/cm2, 6.3%, and 9.8%, respectively, by using the Z-scan and I-scan methods, indicating the tremendous saturable absorption property of 2D VP nanosheets. Furthermore, the passively Q-switched Nd:YVO4 laser was realized with the 2D VP nanosheet-based SA, in which the average output power of 700 mW and the pulse duration of 478 ns were obtained. These results effectively reveal the nonlinear optical absorption characteristics of VP nanosheets, demonstrating their outstanding light-manipulating capabilities and providing a basis for the applications of ultrafast optical devices. Our results verify the excellent saturable absorption properties of 2D VP, paving the way for its applications in pulsed laser generation.

Erratum: Favorable efficacy and reduced acute neurotoxicity by antisense oligonucleotides with 2',4' -BNA/LNA with 9-(aminoethoxy)phenoxazine.

[This corrects the article DOI: 10.1016/j.omtn.2024.102161.].

"One-Pot" Method Preparation of Dendritic Mesoporous Silica-Loaded Matrine Nanopesticide for Noninvasive Administration Control of Monochamus alternatus: The Vector Insect of Bursapherenchus xylophophilus.

Monochamus alternatus is an important stem-boring pest in forestry. However, the complex living environment of Monochamus alternatus creates a natural barrier to chemical control, resulting in a very limited control effect by traditional insecticidal pesticides. In this study, a stable pesticide dendritic mesoporous silica-loaded matrine nanopesticide (MAT@DMSNs) was designed by encapsulating the plant-derived pesticide matrine (MAT) in dendritic mesoporous silica nanoparticles (DMSNs). The results showed that MAT@DMSNs, sustainable nanobiopesticides with high drug loading capacity (80%) were successfully constructed. The release efficiency of DMSNs at alkaline pH was slightly higher than that at acidic pH, and the cumulative release rate of MAT was about 60% within 25 days. In addition, the study on the toxicity mechanism of MAT@DMSNs showed MAT@DMSNs were more effective than MAT and MAT (0.3% aqueous solutions) in touch and stomach toxicity, which might be closely related to their good dispersibility and permeability. Furthermore, MAT@DMSNs are also involved in water transport in trees, which can further transport the plant-derived insecticides to the target site and improve its insecticidal effect. Meanwhile, in addition, the use of essential oil bark penetrants in combination with MAT@DMSNs effectively avoids the physical damage to pines caused by traditional trunk injections and the development of new pests and diseases induced by the traditional trunk injection method, which provides a new idea for the application of biopesticides in the control of stem-boring pests in forestry.

Concentration-Driven Evolution of Adaptive Artificial Ion Channels or Nanopores with Specific Anticancer Activities.

In nature, ceramides are a class of sphingolipids possessing a unique ability to self-assemble into protein-permeable channels with intriguing concentration-dependent adaptive channel cavities. However, within the realm of artificial ion channels, this interesting phenomenon is scarcely represented. Herein, we report on a novel class of adaptive artificial channels, Pn-TPPs, based on PEGylated cholic acids bearing triphenylphosphonium (TPP) groups as anion binding motifs. Interestingly, the molecules self-assemble into chloride ion channels at low concentrations while transforming into small molecule-permeable nanopores at high concentrations. Moreover, the TPP groups endow the molecules with mitochondria-targeting properties, enabling them to selectively drill holes on the mitochondrial membrane of cancer cells and subsequently trigger the caspase 9 apoptotic pathway. The anticancer efficacies of Pn-TPPs correlate with their abilities to form nanopores. Significantly, the most active ensembles formed by P5-TPP exhibits impressive anticancer activity against human liver cancer cells, with an IC50 value of 3.8 µM. While demonstrating similar anticancer performance to doxorubicin, P5-TPP exhibits a selectivity index surpassing that of doxorubicin by a factor of 16.8.

Non-Covalently Stapled H+ /Cl- Ion Channels Activatable by Visible Light for Targeted Anticancer Therapy.

The development of stimuli-responsive artificial H+ /Cl- ion channels, capable of specifically disturbing the intracellular ion homeostasis of cancer cells, presents an intriguing opportunity for achieving high selectivity in cancer therapy. Herein, we describe a novel family of non-covalently stapled self-assembled artificial channels activatable by biocompatible visible light at 442 nm, which enables the co-transport of H+ /Cl- across the membrane with H+ /Cl- transport selectivity of 6.0. Upon photoirradiation of the caged C4F-L for 10 min, 90 % of ion transport efficiency can be restored, giving rise to a 10.5-fold enhancement in cytotoxicity against human colorectal cancer cells (IC50 =8.5 µM). The mechanism underlying cancer cell death mediated by the H+ /Cl- channels involves the activation of the caspase 9 apoptosis pathway as well as the scarcely reported disruption of the autophagic processes. In the absence of photoirradiation, C4F-L exhibits minimal toxicity towards normal intestine cells, even at a concentration of 200 µM.

Change of intracellular calcium level causes acute neurotoxicity by antisense oligonucleotides via CSF route.

Antisense oligonucleotides (ASOs) are promising therapeutics for intractable central nervous system (CNS) diseases. For this clinical application, neurotoxicity is one of the critical limitations. Therefore, an evaluation of this neurotoxicity from a behavioral perspective is important to reveal symptomatic dysfunction of the CNS and elucidate the underlying molecular mechanism. We here exploited a behavioral analysis method to categorize and quantify the acute neurotoxicity of mice administered with toxic ASOs via intracerebroventricular injection. The toxic ASOs were found to reduce consciousness and locomotor function in mice in a dose-dependent manner. Mechanistically, we analyzed the effects of modulators against receptors or channels, which regulate calcium influx of neurons, on the ASO neurotoxicity. Modulators promoting calcium influx mitigated, whereas those hindering calcium influx increased, in vivo neurotoxicity of ASOs in mice. In an in vitro assay to evaluate intracellular free calcium levels using rat primary cortical neurons, toxic ASOs reduced the calcium levels. The findings of this study demonstrated the behavioral characteristics of ASO-induced neurotoxicity and revealed that changes in intracellular free calcium levels are a part of the mechanism underlying the neurotoxic effects of ASO.

Design and Preparation of Avermectin Nanopesticide for Control and Prevention of Pine Wilt Disease.

Pine wilt disease is a devastating forest disaster caused by Bursaphelenchus xylophilus, which has brought inestimable economic losses to the world's forestry due to lack of effective prevention and control measures. In this paper, a porous structure CuBTC was designed to deliver avermectin (AM) and a control vector insect Japanese pine sawyer (JPS) of B. xylophilus, which can improve the biocompatibility, anti-photolysis and delivery efficacy of AM. The results illustrated the cumulative release of pH-dependent AM@CuBTC was up to 12 days (91.9%), and also effectively avoided photodegradation (pH 9.0, 120 h, retention 69.4%). From the traceable monitoring experiment, the AM@CuBTC easily penetrated the body wall of the JPS larvae and was transmitted to tissue cells though contact and diffusion. Furthermore, AM@CuBTC can effectively enhance the cytotoxicity and utilization of AM, which provides valuable research value for the application of typical plant-derived nerve agents in the prevention and control of forestry pests. AM@CuBTC as an environmentally friendly nanopesticide can efficiently deliver AM to the larval intestines where it is absorbed by the larvae. AM@CuBTC can be transmitted to the epidemic wood and dead wood at a low concentration (10 mg/L).

Sustainable nano-pesticide platform based on Pyrethrins II for prevention and control Monochamus alternatus.

BACKGROUND: Pine wilt disease as a devastating forest disaster result from Bursaphelenchus xylophilus that spread by stem-borers Monochamus alternatus feeding on pine leaves, which has brought inestimable economic losses to the world's forestry due to lack of effective prevention and control measures. In this paper, we put forward a proposal for utilizing nanoHKUST-1 to encapusulate the Pyrethrins II that a nerve agent extracted from plant to control M. alternatus, including toxicity mechanism research, traceable biopesticide monitoring, and environment assessment for the first time. The highly biocompatible nanoHKUST-1 can solve the problems of poor water solubility, easy degradation and low control efficiency of Pyrethrins II. RESULTS: The results illustrated the biopesticide loading efficiency of PthII@HKUST-1 reached 85% and the cumulative release of pH-dependent PthII@HKUST-1 was up to 15 days (90%), and also effectively avoid photodegradation (pH 7.0, retention 60.9%). 50 nm PthII@HKUST-1 made it easily penetrate the body wall of MA larvae and transmit to tissue cells through contact and diffusion. Moreover, PthII@HKUST-1 can effectively enhance the cytotoxicity and utilization of Pyrethrins II, which will provide valuable research value for the application of typical plant-derived nerve agents in the prevention and control of forestry pests. PthII@HKUST-1 as an environmentally friendly nano-pesticide can efficiently deliver Pyrethrins II to the larval intestines and absorbed by the larvae. PthII@HKUST-1 could also be transmitted to the epidemic wood and dead wood at a low concentration (10 mg/L). CONCLUSION: Here we speculate that nanoHKUST-1 will bring new opportunity to research biopesticide inhibition mechanism of different agricultural and forestry pests, which will break through the existing research limitations on development, utilization and traceable monitoring of biopesticide, especially for the study of targeting specific proteins.

[Effects of exogenous methylglyoxal on chesnut seedlings under drought stress]. / å¤–æºç”²åŸºä¹™äºŒé†›å¯¹å¹²æ—±èƒè¿«ä¸‹æ¿æ —å¹¼è‹—çš„å½±å“.

Methylglyoxal (MG) is a novel signaling molecule with multiple functions in plants. To explore the effects of MG on Chinese chestnut (Castanea mollissima) under drought stress, two-year-old 'Huangpeng' chestnut seedlings were treated with 15% polyethylene glycol (PEG) coupled with MG or its scavenger N-acetyl-L-cys-teine (NAC). We measured the activities of antioxidant enzymes, including superoxide dismutase (SOD), peroxidase (POD), catalase (CAT), ascorbate peroxidase (APX) and glutathione reductase (GR), and glyoxalase enzymes, including glyoxalase Ⅰ (GlyⅠ) and glyoxalase Ⅱ(GlyⅡ). Contents of antioxidants such as endogenous MG, malondialdehyde (MDA), H2O2, and O2-· as well as the osmotic adjustment substances including proline (Pro), soluble sugar (SS), glycine betaine (GB) were also detected. The results showed that 0.5 mmol·L-1 MG significantly increased the activities of antioxidant enzymes (SOD, POD, CAT, APX, GR) and glyoxalase enzymes (GlyⅠ, GlyⅡ) in leaves of chestnut seedlings under drought stress, elevated the contents of osmotic adjustment substances (Pro, SS, GB) and antioxidant substances (ASA, GSH), and reduced the contents of MG, MDA, H2O2, O2-· and dehydroascorbate (DHA). Drought stress induced damages such as membrane lipid peroxidation and osmotic stress was alleviated by MG, leading to an overall improved adaptability of chestnut to drought stress. Moreover, the addition of MG scavenger NAC could reverse the effects induced by MG, indicating that MG had positive impacts on drought resistance of chestnut plants. Our study provided a theoretical basis for further exploring the mechanism of MG in alleviating drought stress induced symptoms in chestnut.

SKP2 regulates ZEB1 expression and stimulates eutopic endometrial stromal cell invasion and proliferation of adenomyosis.

Though endometriosis is benign, however, it shares certain characteristics with cancers, such as the ability to invade and metastasize. Previous studies have demonstrated that S-phase kinase associated protein2 (SKP2) promotes invasion, tumorigenesis, and metastasis. However, its correlation with adenomyosis is unclear. Herein, we aimed to look into SKP2 expression patterns and regulatory effects on endometrial stromal cell (ESC) proliferation and invasion, and its internal mechanism in adenomyosis. Western blot, qRT-PCR, and immunochemistry were carried out for detecting SKP2 and ZEB1 expression in ESC of adenomyosis and adenomyosis endometrial tissue. The primary ESCs were identified using immunofluorescence. SKP2 knockdown was accomplished in vitro by transfecting a particular lentivirus vector. The colony formation and CCK-8 assays were carried out for assessing cell proliferation, while cell invasion potential was assessed using the transwell assay. Both SKP2 and ZEB1 were found to be significantly upregulated in adenomyosis endometrial tissue. Knockdown of SKP2 inhibited adenomyotic ESC invasion and proliferation. Further experiments showed that knocking out SKP2 reduced ZEB1 expression in adenomyotic ESCs. Our results showed that SKP2 could regulate ZEB1 expression, and increased SKP2 may play a role in the pathogenesis of adenomyosis and stimulating ESC proliferation and invasion.

A new species and key to known species of the genus Conophymacris Willemse, 1933 (Orthoptera, Acridoidea, Catantopidae, Podisminae) from China.

A new species in the genus Conophymacris Willemse, 1933 from Yunnan, China is described. The new species Conophymacris reni sp. nov. is similar to C. jiulongensis Zheng et al., 2009, but differs from latter in width of vertex between eyes of male equal to 2.8 width of frontal ridge between antennae, epiproct of male width longer than length, cercus of male apical part not wider, tegmina extending over the hind margin of first abdominal tergum, hind tibia all red, epiphallus ancorae small, lower than anterior projection, lophi not acute, width of subgenital plate shorter than its length and hind margin with 1 tooth in female. Type specimens are deposited in the Natural Museum of Hebei University, Baoding, Hebei, China.

Role of Sulfur Metabolism Gene and High-Sulfur Gene Expression in Wool Growth Regulation in the Cashmere Goat.

Sulfur, an essential mineral element for animals, mainly exists in the form of organic sulfur-containing amino acids (SAAs), such as cystine, methionine, and cysteine, within the body. The content, form, and structure of sulfur play an important role in determining the wool fiber quality. In addition, keratin-associated proteins, one of the most crucial wool fiber components, are rich in SAAs. However, sulfur metabolism from the blood to the skin and hair follicles remains unclear. In this study, we analyzed high-sulfur protein gene and sulfur metabolism genes in the cashmere goat and explored the effects of melatonin on their expression. In total, 53 high-sulfur protein genes and 321 sulfur metabolism genes were identified. We found that high-sulfur protein genes were distributed in the 3-4 and 144M regions of chromosome 1 and the 40-41M region of chromosome 19 in goats. Moreover, all year round, allele-specific expression (ASE) is higher in the 40-41M region of chromosome 19 than in the other regions. Total of 47 high-sulfur protein genes showed interaction with transcription factors and cofactors with ASE. These transcription factors and cofactors were inhibited after melatonin implantation. The network analysis revealed that melatonin may activate the sulfur metabolism process via the regulation of the genes related to cell energy metabolism and cell cycle in the skin, which provided sufficient SAAs for wool and cashmere growth. In conclusion, our findings provide a new insight into wool growth regulation by sulfur metabolism genes and high-sulfur protein genes in cashmere goats.

A simple signal-on strategy for fluorescent detection of tuberculostatic drug isoniazid based on Ag clusters-MnO2 sheets nanoplatform.

As a first-line tuberculostatic drug, isoniazid (INH) plays effective and irreplaceable role in prevention and treatment of tuberculosis. In this work, a rapid and simple signal-on fluorescence approach is established for INH assay by employing a platform composed of silver nanoclusters (AgNCs) and MnO2 nanosheets. In the proposed sensing system, strong red fluorescence of poly (methacrylic acid)-stabilized AgNCs can be greatly quenched after they attach to the surfaces of MnO2 nanosheets. With the addition of INH, MnO2 nanosheets are reduced to Mn2+ and subsequently release the AgNCs, which leads to obvious fluorescence recovery again. Based on this mechanism, highly sensitive detection of INH in the range of 0.8-200 µM is realized (detection limit: 476 nM). The present strategy shows remarkable advantages including simplicity, rapidness, high sensitivity and wide detectable range. This method is also practical and comparable to high-performance liquid chromatography, which can be applied to detect INH in human urine and serum samples as well as pharmaceutical products.

Self-assembled bovine serum albumin nanoparticles as pesticide delivery vectors for controlling trunk-boring pests.

BACKGROUND: Trunk-boring pests (TBPs) are an important type of forest pest, TBPs not only feed on the branches and trunks of trees, but also spread quarantine diseases in forests. However, because the larvae of TBPs live inside the trunk and are well concealed, prevention and control are difficult. The lack of effective control methods leads to the death of many trees in forests. In this study, a novel nanopesticide featuring high bioactivity and slow-release properties was developed to control TBPs. Thiacloprid (THI), which is commonly used to control Coleoptera species, was used as a model pesticide. RESULTS: The oleophobic properties of bovine serum albumin (BSA) were exploited to encapsulate the hydrophobic pesticide THI by self-assembly, and the size of the obtained nanoparticles, THI@BSA·NPs, was approximately 23 nm. The loading efficiency reached 70.4%, and THI@BSA·NPs could be released continuously for over 15 days, with the cumulative release reaching 93.5%. The fluorescein isothiocyanate (FITC)-labeled nanoparticles were evenly distributed in the digestive tract and body surface of a typical TBPs, M. alternatus, and the stomach and contact toxicities increased by 33.7% and 25.9%, respectively, compared with those of free THI. Furthermore, the results showed that the transport efficiency of THI@BSA·NPs was highest at a concentration of 50 µg/mL, and the THI@BSA·NPs content in the trunk, from to lower to higher layers, was 8.8, 8.2, 7.6, and 5.8 µg/g. At the same time, THI@BSA·NPs also exhibited high transport efficiency in dead trees. CONCLUSION: The transport efficiency and toxicity of the active ingredients are the key factors for the control of TBPs. This work provided idea for the application of biological delivery system encapsulated hydrophobic pesticides. The novel self-assembled THI@BSA·NPs have promising potential for sustainable control of TBPs.

Targeting drug delivery system for platinum(â £)-Based antitumor complexes.

Classical platinum(II) anticancer agents are widely-used chemotherapeutic drugs in the clinic against a range of cancers. However, severe systemic toxicity and drug resistance have become the main obstacles which limit their application and effectiveness. Because divalent cisplatin analogues are easily destroyed in vivo, their bioavailability is low and no selective to tumor tissues. The platinum(IV) prodrugs are attractive compounds for cancer treatment because they have great advantages, e.g., higher stability in biological media, aqueous solubility and no cross-resistance with cisplatin, which may become the next generation of platinum anticancer drugs. In addition, platinum(IV) drugs could be taken orally, which could be more acceptable to cancer patients, breaking the current situation that platinum(II) drugs can only be given by injection. The coupling of platinum(IV) complexes with tumor targeting groups avoids the disadvantages such as instability in blood, irreversible binding to plasma proteins, rapid renal clearance, and non-specific distribution in normal tissues. Because of the above advantages, the combination of platinum complexes and tumor targeting groups has become the hottest field in the research and development of new platinum drugs. These approaches can be roughly categorized into two groups: active and passive targeted strategies. This review concentrates on various targeting and delivery strategies for platinum(IV) complexes to improve the efficacy and reduce the side effects of platinum-based anticancer drugs. We have made a summary of the related articles on platinum(IV) targeted delivery in recent years. We believe the results of the studies described in this review will provide new ideas and strategies for the development of platinum drugs.

Highly efficient gene silencing in mouse brain by overhanging-duplex oligonucleotides via intraventricular route.

Gapmer-type antisense oligonucleotides have not yet been approved for the treatment of central nervous system diseases, whereas steric-blocking-type antisense oligonucleotides have been well-developed for clinical use. We here characterize a new type of double-stranded oligonucleotides, overhanging-duplex oligonucleotides, which are composed of the parent gapmer and its extended complementary RNA. By intracerebroventricular injection, overhanging oligonucleotides show greater silencing potency with more efficient delivery into mouse brains than the parent single-stranded gapmer. Structure-activity relationship analyses reveal that the potency enhancement requires 13-mer or more overhanging oligonucleotides with a phosphorothioate backbone. Overhanging oligonucleotides provide a new platform of therapeutic oligonucleotides for gene modulation in the central nervous system.

Detection of tiopronin in body fluids and pharmaceutical products using red-emissive DNA-stabilized silver nanoclusters as a fluorescent probe.

Tiopronin is a widely used drug for treatment of cystinuria, rheumatoid arthritis and hepatic disorders. It is also an antidote to heavy metal poisoning and a radioprotective agent. A method is described for rapid and sensitive determination of tiopronin using DNA-stabilized silver nanoclusters (DNA-AgNCs) as a fluorescent probe. Tiopronin can selectively bind to DNA-AgNCs to form a stable Ag-S bond upon which the red photoluminescence (best measured at excitation/emission wavelengths of 590/640 nm) is quenched. The finding is used to design an assay that has a linear response in the 1-150 nM tiopronin concentration range and a 270 pM limit of detection. Compared with previously reported methods, the present approach is more rapid, highly sensitive and selective. It has been successfully applied in the detection of tiopronin in spiked urine and serum, and in pharmaceutical products (tablets and injections). Graphical abstract An ultrasensitive and reliable method for tiopronin assay is developed using red-emissive silver nanoclusters as a fluorescent probe. It has been successfully applied in the determination of tiopronin in biological fluids and pharmaceutical products.

7kW direct-liquid-cooled side-pumped Nd:YAG multi-disk laser resonator.

A direct-liquid-cooled side-pumped Nd:YAG multi-disk QCW laser resonator is presented, in which the oscillating laser propagates through multiple thin disks and cooling flow layers in Brewster angle. Twenty Nd:YAG thin disks side-pumped by LD arrays are directly cooled by flowing deuteroxide at the end surfaces. A laser output with the highest pulse energy of 17.04 J is obtained at the pulse width of 250 µs and repetition rate of 25 Hz, corresponding to an optical-optical efficiency of 34.1% and a slope efficiency of 44.5%. The maximum average output power of 7.48 kW is achieved at the repetition rate of 500 Hz. Due to thermal effects, the corresponding optical-optical efficiency decreases to 30%. Under the 12.5 kW pumping condition while not oscillating, the wavefront of a He-Ne probe passing through the gain module is as low as 0.256 µm (RMS) with the defocus and tetrafoil subtracted.