Spatially Asymmetric Nanoparticles for Boosting Ferroptosis in Tumor Therapy.

Despite its effectiveness in eliminating cancer cells, ferroptosis is hindered by the high natural antioxidant glutathione (GSH) levels in the tumor microenvironment. Herein, we developed a spatially asymmetric nanoparticle, Fe3O4@DMS&PDA@MnO2-SRF, for enhanced ferroptosis. It consists of two subunits: Fe3O4 nanoparticles coated with dendritic mesoporous silica (DMS) and PDA@MnO2 (PDA: polydopamine) loaded with sorafenib (SRF). The spatial isolation of the Fe3O4@DMS and PDA@MnO2-SRF subunits enhances the synergistic effect between the GSH-scavengers and ferroptosis-related components. First, the increased exposure of the Fe3O4 subunit enhances the Fenton reaction, leading to increased production of reactive oxygen species. Furthermore, the PDA@MnO2-SRF subunit effectively depletes GSH, thereby inducing ferroptosis by the inactivation of glutathione-dependent peroxidases 4. Moreover, the SRF blocks Xc- transport in tumor cells, augmenting GSH depletion capabilities. The dual GSH depletion of the Fe3O4@DMS&PDA@MnO2-SRF significantly weakens the antioxidative system, boosting the chemodynamic performance and leading to increased ferroptosis of tumor cells.

Bioactive decellularized adipose matrix prepared using a rapid, nonchemical/enzymatic method for adipogenesis.

Recent developments in the field of regenerative surgeries and medical applications have led to a renewed interest in adipose tissue-enriched mesenchymal stem cell scaffolds. Various advantages declared for the decellularized adipose matrix (DAM) have caused its extensive use in the transfer of stem cells or growth factors for soft tissue regeneration induction. Meanwhile, the long-term application of detergents toward DAM regeneration has been assumed as a risky obstacle in this era. Herein, a rapid, mechanical protocol was developed to prepare DAM (M-DAM) without chemicals/enzymes and was comprehensively compared with the ordinary DAM (traditional chemical method). Accordingly, this method could effectively hinder oils and cells, sustain the structural and biological elements, and contain a superior level of collagen content. In addition, more protein numbers, as well as higher basement membrane elements, glycoproteins, and extracellular matrix-related proteins were detected in the regenerated M-DAM. Also, superior adipogenesis and angiogenesis proteins were distinguished. The noncytotoxicity of the M-DAM was also approved, and a natural ecological niche was observed for the proliferation and differentiation of stem cells, confirming its great potential for vascularization and adipogenesis in vivo. The suggested technique could effectively prepare the modified DAM in variant constructions of tablets, powders, emulsions, hydrogels, and different three-dimensional-printed structures. Hence, this rapid, mechanical process can produce bioactive DAM, which has the potential to be widely used in various research fields of regenerative medicine.

Regulated stepwise ESDPT mechanism associated with chalcogen substitutions in BDIBD derivatives.

Inspired by the brilliant photochemical and photophysical properties of organic molecules containing chalcogenide substitutions that could be potentially applied across various disciplines, in this work, the effects of the atomic electronegativity of chalcogens (O, S, and Se) on hydrogen bond interactions and excited state proton transfer (ESPT) are mainly focused. We present characteristic oxygen-hydroxybenzazole-substituted 2,5-bis(4,5-diphenyl-1H-imidazol-2-yl)benzene-1,4-diol (BDIBD) derivatives that contain intramolecular double hydrogen bonds. The main objective of this study was to explore in detail the influence of the change of chalcogen atomic electronegativity on dual hydrogen bond interaction and ESPT behavior. By comparing the structural changes and infrared (IR) vibrational spectra of BDIBD derivative (BDIBD-O, BDIBD-S and BDIBD-Se) fluorophores in S0 and S1 states, combined with the preliminary detection of hydrogen bond interaction via the core-valence bifurcation (CVB) index and predicted hydrogen bonding energy (EHB), we conclude that dual hydrogen bonds should be strengthened in the S1 state, which is favorable for the occurrence of ESPT reactions. The charge recombination behavior of hydrogen bonds, induced by photoexcitation, further illustrates this point. By constructing potential energy surfaces (PESs) based on restrictive optimization and by searching the transition state (TS) structure, we finally elucidate stepwise excited-state double proton transfer (ESDPT). Specifically, we confirm that a change in atomic electronegativity has a regulatory effect on the ESDPT behavior in BDIBD derivatives, that is, lower atomic electronegativity is more conducive to stepwise ESDPT.

Dual Network Hydrogels Based on PRP and SA Promote the Retention Rate and Vascularization of Transplanted Fat.

BACKGROUND: Autologous adipose tissue often experiences ischemia and hypoxia after transplantation, leading to low retention rates and unstable operative impacts due to necrotic absorption. Platelet-rich plasma (PRP) can enhance fat regeneration and increase the fat retention rate after transplantation. However, the quick release of growth factors (GFs) in PRP decreases therapeutic efficiency. This study aimed to achieve a slow release of PRP to promote fat retention. METHODS: We prepared a dual-network hydrogel (DN gel) based on FDA-approved PRP and sodium alginate (SA) through a simple "one-step" activation process. In vivo study, adipose tissue with saline (control group), SA gel (SA gel group), PRP gel (PRP gel group), and DN gel (DN gel group) was injected subcutaneously into the dorsum of nude mice. At 4 and 12 weeks after injection, tissues were assessed for volume and weight. Hematoxylin and eosin staining (HE) and immunofluorescence staining were performed for histological assessment. RESULTS: DN gel exhibits long-lasting growth factor effects, surpassing conventional clinical PRP gel regarding vascularization potential. In fat transplantation experiments, DN gel demonstrated improved vascularization of transplanted fat and increased retention rates, showing promise for clinical applications. CONCLUSIONS: DN gel-assisted lipofilling can significantly improve the retention rate and quality of transplanted fat. DN gel-assisted lipofilling, which is considered convenient, is a promising technique to improve neovascularization and fat survival. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each submission to which Evidence-Based Medicine rankings are applicable. This excludes Review Articles, Book Reviews, and manuscripts that concern Basic Science, Animal Studies, Cadaver Studies, and Experimental Studies. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Surface curvature-induced oriented assembly of sushi-like Janus therapeutic nanoplatform for combined chemodynamic therapy.

BACKGROUND: Chemodynamic therapy (CDT) based on Fenton/Fenton-like reaction has emerged as a promising cancer treatment strategy. Yet, the strong anti-oxidation property of tumor microenvironment (TME) caused by endogenous glutathione (GSH) still severely impedes the effectiveness of CDT. Traditional CDT nanoplatforms based on core@shell structure possess inherent interference of different subunits, thus hindering the overall therapeutic efficiency. Consequently, it is urgent to construct a novel structure with isolated functional units and GSH depletion capability to achieve desirable combined CDT therapeutic efficiency. RESULTS: Herein, a surface curvature-induced oriented assembly strategy is proposed to synthesize a sushi-like novel Janus therapeutic nanoplatform which is composed of two functional units, a FeOOH nanospindle serving as CDT subunit and a mSiO2 nanorod serving as drug-loading subunit. The FeOOH CDT subunit is half covered by mSiO2 nanorod along its long axis, forming sushi-like structure. The FeOOH nanospindle is about 400 nm in length and 50 nm in diameter, and the mSiO2 nanorod is about 550 nm in length and 100 nm in diameter. The length and diameter of mSiO2 subunit can be tuned in a wide range while maintaining the sushi-like Janus structure, which is attributed to a Gibbs-free-energy-dominating surface curvature-induced oriented assembly process. In this Janus therapeutic nanoplatform, Fe3+ of FeOOH is firstly reduced to Fe2+ by endogenous GSH, the as-generated Fe2+ then effectively catalyzes overexpressed H2O2 in TME into highly lethal ·OH to achieve efficient CDT. The doxorubicin (DOX) loaded in the mSiO2 subunit can be released to achieve combined chemotherapy. Taking advantage of Fe3+-related GSH depletion, Fe2+-related enhanced ·OH generation, and DOX-induced chemotherapy, the as-synthesized nanoplatform possesses excellent therapeutic efficiency, in vitro eliminating efficiency of tumor cells is as high as ~ 87%. In vivo experiments also show the efficient inhibition of tumor, verifying the synthesized sushi-like Janus nanoparticles as a promising therapeutic nanoplatform. CONCLUSIONS: In general, our work provides a successful paradigm of constructing novel therapeutic nanoplatform to achieve efficient tumor inhibition.

Heme oxygenase 1 alleviates nonalcoholic steatohepatitis by suppressing hepatic ferroptosis.

BACKGROUND: Heme oxygenase 1 (HO-1) has an influential but insufficiently investigated effect on ferroptosis, which is a novel form of programmed cell death and may play an effect on nonalcoholic steatohepatitis (NASH). However, the understanding of the mechanism is limited. Herein, our study aimed to explore the mechanism and role of HO-1 in NASH ferroptosis. METHODS: Hepatocyte conditional HO-1 knockout (HO-1HEPKO) C57BL/6J mice were established and fed a high-fat diet (HFD). Additionally, wild-type mice were fed either a normal diet or a HFD. Hepatic steatosis, inflammation, fibrosis, lipid peroxidation, and iron overload were assessed. AML12 and HepG2 cells were used to investigate the underlying mechanisms in vitro. Finally, liver sections from NASH patients were used to clinically validate the histopathology of ferroptosis. RESULTS: In mice, HFD caused lipid accumulation, inflammation, fibrosis, and lipid peroxidation, which were aggravated by HO-1HEPKO. In line with the in vivo results, HO-1 knockdown upregulated reactive oxygen species accumulation, lipid peroxidation, and iron overload in AML12 and HepG2 cells. Additionally, HO-1 knockdown reduced the GSH and SOD levels, which was in contrast to HO-1 overexpression in vitro. Furthermore, the present study revealed that the NF-κB signaling pathway was associated with ferroptosis in NASH models. Likewise, these findings were consistent with the liver histopathology results of NASH patients. CONCLUSION: The current study showed that HO-1 could alleviate NASH progression by mediating ferroptosis.

[Comprehensive evaluation of Pinellia ternata germplasm resources based on phenotypic trait classification].

The evaluation of germplasm resources is the prerequisite for the development, utilization, and conservation of Chinese medicinal resources. The selection of excellent germplasm is the key to the breeding and orderly production of Pinellia ternata. In this study, 21 germplasm materials of P. ternata from major production areas in China were collected and analyzed for population diversity after phenotypic preliminary screening. The results have revealed that the P. ternata population has abundant phenotypic variation, and the phenotypic changes could be divided into five phenotypes in terms of organ trait variation. Further analysis of variation in 20 quantitative traits of the population revealed that the coefficient of variation for adenosine content(339.05%) was the largest, while the coefficient of variation for the underground plant height(16.35%) was the smallest. Correlation analysis showed that there was a strong correlation among various traits, with 52 pairs of traits showing highly significant correlation(P<0.01) and 19 pairs of traits showing a significant correlation(P<0.05). The 21 germplasms in the test could be classified into three major clusters by cluster analysis, with Cluster Ⅱ having the highest number and content of nucleosides, making it suitable for the selection and breeding of P. ternata varieties with high content of nucleosides. The yield in Cluster Ⅲ was higher than that in other groups, making it suitable for the selection and breeding of P. ternata varieties with a high yield. All trait indicators could be simplified into five principal component factors through principal component analysis, and the cumulative contribution rate was up to 86.04%. Further, comprehensive analysis using membership function and stepwise regression analysis identified nine traits, such as plant height, main leaf length, and underground plant height as characteristic indicators for the comprehensive evaluation of germplasm resources of P. ternata. BX007, BX008, and BX005 were identified as germplasms with both high yield and high uridine content, with BX007 having the highest uridine content of 479.51 µg·g~(-1). It belonged to the germplasm of P. ternata with double bulbils and could be cultivated as a potential good variety. Based on the phenotypic classification of P. ternata, systematic resource evaluation was carried out in this study, which could lay a foundation for the excavation of genetic resources and the breeding of new varieties of P. ternata.

Cascading Alignment for Unsupervised Domain-Adaptive DETR with Improved DeNoising Anchor Boxes.

Transformer-based object detection has recently attracted increasing interest and shown promising results. As one of the DETR-like models, DETR with improved denoising anchor boxes (DINO) produced superior performance on COCO val2017 and achieved a new state of the art. However, it often encounters challenges when applied to new scenarios where no annotated data is available, and the imaging conditions differ significantly. To alleviate this problem of domain shift, in this paper, unsupervised domain adaptive DINO via cascading alignment (CA-DINO) was proposed, which consists of attention-enhanced double discriminators (AEDD) and weak-restraints on category-level token (WROT). Specifically, AEDD is used to aggregate and align the local-global context from the feature representations of both domains while reducing the domain discrepancy before entering the transformer encoder and decoder. WROT extends Deep CORAL loss to adapt class tokens after embedding, minimizing the difference in second-order statistics between the source and target domain. Our approach is trained end to end, and experiments on two challenging benchmarks demonstrate the effectiveness of our method, which yields 41% relative improvement compared to baseline on the benchmark dataset Foggy Cityscapes, in particular.

Crosstalk between alternative polyadenylation and miRNAs in the regulation of protein translational efficiency.

3' UTRs play important roles in the gene regulation network via their influence on mRNA stability, translational efficiency, and subcellular localization. For a given gene, 3' UTRs of different lengths generated by alternative polyadenylation (APA) may result in functional differences in regulation. The mechanistic details of how length changes of 3' UTRs alter gene function remain unclear. By combining APA sequencing and polysome profiling, we observed that mRNA isoforms with shorter 3' UTRs were bound with more polysomes in six cell lines but not in NIH3T3 cells, suggesting that changing 3' UTRs to shorter isoforms may lead to a higher gene translational efficiency. By interfering with the expression of TNRC6A and analyzing AGO2-PAR-CLIP data, we revealed that the APA effect on translational efficiency was mainly regulated by miRNAs, and this regulation was cell cycle dependent. The discrepancy between NIH3T3 and other cell lines was due to contact inhibition of NIH3T3. Thus, the crosstalk between APA and miRNAs may be needed for the regulation of protein translational efficiency.

OsPIN9, an auxin efflux carrier, is required for the regulation of rice tiller bud outgrowth by ammonium.

The degree of rice tillering is an important agronomic trait that can be markedly affected by nitrogen supply. However, less is known about how nitrogen-regulated rice tillering is related to polar auxin transport. Compared with nitrate, ammonium induced tiller development and was paralleled with increased 3 H-indole-acetic acid (IAA) transport and greater auxin into the junctions. OsPIN9, an auxin efflux carrier, was selected as the candidate gene involved in ammonium-regulated tillering based on GeneChip data. Compared with wild-type plants, ospin9 mutants had fewer tillers, and OsPIN9 overexpression increased the tiller number. Additionally, OsPIN9 was mainly expressed in vascular tissue of the junction and tiller buds, and encoded a membrane-localised protein. Heterologous expression in Xenopus oocytes and yeast demonstrated that OsPIN9 is a functional auxin efflux transporter. More importantly, its RNA and protein levels were induced by ammonium but not by nitrate, and tiller numbers in mutants did not respond to nitrogen forms. Further advantages, including increased tiller number and grain yield, were observed in overexpression lines grown in the paddy field at a low-nitrogen rate compared with at a high-nitrogen rate. Our data revealed that ammonium supply and an auxin efflux transporter co-ordinately control tiller bud elongation in rice.

Severe Vascular Complications Caused by Facial Autologous Fat Grafting: A Critical Review.

BACKGROUND: Vascular embolism is the most severe complication after autologous fat grafting. With a worldwide increase in fat grafting, there has been a rise in severe vascular complications, such as ophthalmic artery embolism, cerebral artery embolism, and even death. This article aims to review the role of fat in causing severe vascular complications and the association between fat grafting and severe vascular complications. METHODS: A critical review was conducted by appraising the cases of severe vascular complications associated with facial fat grafting reported globally. Repeated cases that were reported in multiple publications were further screened. RESULTS: The final search yielded 50 publications in English that met the inclusion criteria for review. A total of 113 cases of fat-induced severe vascular complications in the literature were identified. The number of cases reported yearly has increased over time, with even more significant increases since 2010. The glabella and temple are the most common sites of severe vascular complications described in the literature. In addition, only one case of ophthalmic artery embolism and one case of cerebral artery embolism have been treated successfully. CONCLUSIONS: Given the increase in reported cases of severe vascular complications, both doctors and patients should pay careful attention to the risks of facial fat grafting. Because of the unclear mechanism of vascular embolism and the lack of guidelines for prevention and treatment, the effective cure rate is unsatisfactory. We propose that preventing vascular embolism is a priority in fat grafting and that timely, multidisciplinary treatment should be performed when severe vascular complications occur. It is necessary in future studies to explore the mechanisms of vascular embolism and effective treatment strategies to promote the development of fat grafting.

Molecular Regulatory Networks for Improving Nitrogen Use Efficiency in Rice.

Nitrogen is an important factor limiting the growth and yield of rice. However, the excessive application of nitrogen will lead to water eutrophication and economic costs. To create rice varieties with high nitrogen use efficiency (NUE) has always been an arduous task in rice breeding. The processes for improving NUE include nitrogen uptake, nitrogen transport from root to shoot, nitrogen assimilation, and nitrogen redistribution, with each step being indispensable to the improvement of NUE. Here, we summarize the effects of absorption, transport, and metabolism of nitrate, ammonium, and amino acids on NUE, as well as the role of hormones in improving rice NUE. Our discussion provide insight for further research in the future.

Highly Porous Silk Fibroin Scaffold Packed in PEGDA/Sucrose Microneedles for Controllable Transdermal Drug Delivery.

Polymeric microneedles have attracted increasing attention as a minimally invasive platform for delivering drugs or vaccines in a more patient-friendly manner. However, traditional microfabrication techniques using negative molds with needle-shaped cavities usually require cumbersome centrifugation and vacuum degassing processes, which have restricted the scaled-up mass production of polymeric microneedles. Herein, a novel polydimethylsiloxane (PDMS)-based negative mold with cavities packed with silk fibroin scaffold is developed for rapid fabrication of polymeric microneedles, which comprise primarily the composition of poly(ethylene glycol) diacrylate (PEGDA) and sucrose as the needle matrix. Fibroin scaffolds can instantly adsorb prepolymer solution due to capillary force, and subsequently initiate the formation of microneedles via photoinduced polymerization. Based on three types of model drugs, including Rhodamine B (RhB), indocyanine green (ICG), and doxorubicin (DOX), the fabricated PEGDA/sucrose microneedles can realize effective transdermal delivery and controllable release of therapeutic molecules by regulating the sucrose content. The presented method provides a simple strategy for quick fabrication of polymeric microneedles toward transdermal drug delivery applications.

PEGylated mesoporous Bi2S3 nanostars loaded with chlorin e6 and doxorubicin for fluorescence/CT imaging-guided multimodal therapy of cancer.

Taking advantage of the mesoporous structure of bismuth sulfide nanostars (Bi2S3 NSs), a chemotherapeutic drug of doxorubicin (DOX) and a photosensitizer of chlorin e6 (Ce6) were concurrently loaded in the PEGylated Bi2S3 NSs to formulate a multifunctional nanocomplex (BPDC NSs) for tumor theranostics. BPDC NSs have excellent photothermal conversion efficiency and a capacity of yielding reactive oxygen species (ROS) upon laser irradiation, and can realize on-demand drug release by either pH-activation or thermal induction. Accumulation of the nanodrug could be monitored in real-time by infrared thermal imaging, fluorescence imaging and computed tomography (CT). More importantly, the combination effects of photothermal therapy (PTT), photodynamic therapy (PDT) and chemotherapy were demonstrated to dramatically suppress solid tumors without recurrence in vivo. Featuring low systemic toxicity and high biocompatibility, this nanoplatform could be a promising derivative of Bi2S3 NSs for imaging-guided theranostics of cancer.

A paper-based photothermal array using Parafilm to analyze hyperthermia response of tumour cells under local gradient temperature.

Temperature is a critical extrinsic physical parameter that determines cell fate. Hyperthermia therapy has become an efficient treatment for tumor ablation. To understand the response of tumor cells under thermal shocks, we present a paper-based photothermal array that can be conveniently coupled with commercial 96-well cell culture plates. This paper chip device was fabricated in one step using Parafilm® and Kimwipers® based on a heat lamination strategy. Liquid was completely adsorbed and confined within the cellulose fibres of hydrophilic regions. Then, Prussian blue nanoparticles (PB NPs) as the photothermal initiator were introduced into the loading wells, and thermal energy was generated via near infrared (NIR) laser irradiation. After assembling the paper device with a 96-well plate, the temperature of each well could be individually controlled by varying the loading amount of PB NPs and laser irradiation time. As a proof-of-concept study, the effects of local thermal shocks on HeLa cells were investigated using MTT cell viability assay and Live/Dead cell staining. The variation of cell viability could be monitored in situ with controllable temperature elevation. The proposed paper photothermal array loaded with thermal initiators represents an enabling tool for investigating the hyperthermia responses of biological cells. Moreover, the facile fabrication technique for paper patterning is advantageous for customizing high-throughput microfluidic paper-based analytical devices (µPADs) with extremely low cost.

Strigolactones are required for nitric oxide to induce root elongation in response to nitrogen and phosphate deficiencies in rice.

The response of the root system architecture to nutrient deficiencies is critical for sustainable agriculture. Nitric oxide (NO) is considered a key regulator of root growth, although the mechanisms remain unknown. Phenotypic, cellular and genetic analyses were undertaken in rice to explore the role of NO in regulating root growth and strigolactone (SL) signalling under nitrogen-deficient and phosphate-deficient conditions (LN and LP). LN-induced and LP-induced seminal root elongation paralleled NO production in root tips. NO played an important role in a shared pathway of LN-induced and LP-induced root elongation via increased meristem activity. Interestingly, no responses of root elongation were observed in SL d mutants compared with wild-type plants, although similar NO accumulation was induced by sodium nitroprusside (SNP) application. Application of abamine (the SL inhibitor) reduced seminal root length and pCYCB1;1::GUS expression induced by SNP application in wild type; furthermore, comparison with wild type showed lower SL-signalling genes in nia2 mutants under control and LN treatments and similar under SNP application. Western blot analysis revealed that NO, similar to SL, triggered proteasome-mediated degradation of D53 protein levels. Therefore, we presented a novel signalling pathway in which NO-activated seminal root elongation under LN and LP conditions, with the involvement of SLs.

Nitric oxide generated by nitrate reductase increases nitrogen uptake capacity by inducing lateral root formation and inorganic nitrogen uptake under partial nitrate nutrition in rice.

Increasing evidence shows that partial nitrate nutrition (PNN) can be attributed to improved plant growth and nitrogen-use efficiency (NUE) in rice. Nitric oxide (NO) is a signalling molecule involved in many physiological processes during plant development and nitrogen (N) assimilation. It remains unclear whether molecular NO improves NUE through PNN. Two rice cultivars (cvs Nanguang and Elio), with high and low NUE, respectively, were used in the analysis of NO production, nitrate reductase (NR) activity, lateral root (LR) density, and (15)N uptake under PNN, with or without NO production donor and inhibitors. PNN increased NO accumulation in cv. Nanguang possibly through the NIA2-dependent NR pathway. PNN-mediated NO increases contributed to LR initiation, (15)NH4(+)/(15)NO3(-) influx into the root, and levels of ammonium and nitrate transporters in cv. Nanguang but not cv. Elio. Further results revealed marked and specific induction of LR initiation and (15)NH4(+)/(15)NO3(-) influx into the roots of plants supplied with NH4(+)+sodium nitroprusside (SNP) relative to those supplied with NH4(+) alone, and considerable inhibition upon the application of cPTIO or tungstate (NR inhibitor) in addition to PNN, which is in agreement with the change in NO fluorescence in the two rice cultivars. The findings suggest that NO generated by the NR pathway plays a pivotal role in improving the N acquisition capacity by increasing LR initiation and the inorganic N uptake rate, which may represent a strategy for rice plants to adapt to a fluctuating nitrate supply and increase NUE.

A strigolactone signal is required for adventitious root formation in rice.

BACKGROUND AND AIMS: Strigolactones (SLs) and their derivatives are plant hormones that have recently been identified as regulating root development. This study examines whether SLs play a role in mediating production of adventious roots (ARs) in rice (Oryza sativa), and also investigates possible interactions between SLs and auxin. METHODS: Wild-type (WT), SL-deficient (d10) and SL-insensitive (d3) rice mutants were used to investigate AR development in an auxin-distribution experiment that considered DR5::GUS activity, [(3)H] indole-3-acetic acid (IAA) transport, and associated expression of auxin transporter genes. The effects of exogenous application of GR24 (a synthetic SL analogue), NAA (α-naphthylacetic acid, exogenous auxin) and NPA (N-1-naphthylphalamic acid, a polar auxin transport inhibitor) on rice AR development in seedlings were investigated. KEY RESULTS: The rice d mutants with impaired SL biosynthesis and signalling exhibited reduced AR production compared with the WT. Application of GR24 increased the number of ARs and average AR number per tiller in d10, but not in d3. These results indicate that rice AR production is positively regulated by SLs. Higher endogenous IAA concentration, stronger expression of DR5::GUS and higher [(3)H] IAA activity were found in the d mutants. Exogenous GR24 application decreased the expression of DR5::GUS, probably indicating that SLs modulate AR formation by inhibiting polar auxin transport. The WT and the d10 and d3 mutants had similar expression of DR5::GUS regardless of exogenous application of NAA or NPA; however, AR number was greater in the WT than in the d mutants. CONCLUSIONS: The results suggest that AR formation is positively regulated by SLs via the D3 response pathway. The positive effect of NAA application and the opposite effect of NPA application on AR number of WT plants also suggests the importance of auxin for AR formation, but the interaction between auxin and SLs is complex.

Qingnaoyizhi decoction suppresses the formation of glial fibrillary acidic protein-positive cells in cultured neural stem cells by inhibiting the Janus kinase 2/signal transducer and activator of transcription 3 signaling pathway.

OBJECTIVE: Inactivation of the Janus kinase 2 in treated NSCs. Furthermore, QNYZD may play a direct role in suppressing the formation of GFAP-positive cells and enhancing neuronal differentiation by inhibiting JAK2/STAT3 activation. Overall, these results provide insights into the possible mechanism underlying QNYZD-mediated neurogenesis. (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling axis plays a crucial role in determining the fate of neural stem cells (NSCs). Qingnaoyizhi decoction (QNYZD) has been used for the treatment of vascular dementia and has shown to improve synaptic remodeling. The aim of this study was to evaluate the effect of cerebrospinal fluid (CSF) containing QNYZD (CSF-QNYZD) on the differentiation of cultured NSCs and the involvement of the JAK2/STAT3 pathway. METHODS: The protein expression levels of glial fibrillary acidic protein (GFAP), tubulin, drosophila mothers against decapentaplegic protein (SMAD-1), STAT3, and phosphorylated-STAT3 were detected by western immunoblot analysis in the groups: control, CSF, JAK/STAT inhibitor (AG490), CSF-QNYZD, and CSF-XDZ (CSF-Xidezhen). The differentiation of NSCs was determined by immunofluorescence staining. The proliferation of NSCs was measured using the Cell Counting Kit-8 proliferation assay. RESULTS: Compared with the control group, CSF-QNYZD and AG490 significantly increased the number and expression of tubulin-positive cells, reduced the number and expression of GFAP-positive cells, and down-regulated the expression of p-STAT3. However, CSF-QNYZD also decreased the expression of SMAD-1 and STAT3. CONCLUSION: Enhanced neuronal differentiation may be associated with the down-regulation of glial differentiation instead of promoting proliferation in treated NSCs. Furthermore, QNYZD may play a direct role in suppressing the formation of GFAP-positive cells and enhancing neuronal differentiation by inhibiting JAK2/STAT3 activation. Overall, these results provide insights into the possible mechanism underlying QNYZD-mediated neurogenesis.

Black Titania Janus Mesoporous Nanomotor for Enhanced Tumor Penetration and Near-Infrared Light-Triggered Photodynamic Therapy.

Thanks to their excellent photoelectric characteristics to generate cytotoxic reactive oxygen species (ROS) under the light-activation process, TiO2 nanomaterials have shown significant potential in photodynamic therapy (PDT) for solid tumors. Nevertheless, the limited penetration depth of TiO2-based photosensitizers and excitation sources (UV/visible light) for PDT remains a formidable challenge when confronted with complex tumor microenvironments (TMEs). Here, we present a H2O2-driven black TiO2 mesoporous nanomotor with near-infrared (NIR) light absorption capability and autonomous navigation ability, which effectively enhances solid tumor penetration in NIR light-triggered PDT. The nanomotor was rationally designed and fabricated based on the Janus mesoporous nanostructure, which consists of a NIR light-responsive black TiO2 nanosphere and an enzyme-modified periodic mesoporous organosilica (PMO) nanorod that wraps around the TiO2 nanosphere. The overexpressed H2O2 can drive the nanomotor in the TME under catalysis of catalase in the PMO domain. By precisely controlling the ratio of TiO2 and PMO compartments in the Janus nanostructure, TiO2&PMO nanomotors can achieve optimal self-propulsive directionality and velocity, enhancing cellular uptake and facilitating deep tumor penetration. Additionally, by the decomposition of endogenous H2O2 within solid tumors, these nanomotors can continuously supply oxygen to enable highly efficient ROS production under the NIR photocatalysis of black TiO2, leading to intensified PDT effects and effective tumor inhibition.