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Tribulus terrestris L. is an annual herbaceous medicinal plant of Zygophyllaceae, which is cultivated commercially in China. Subrotund or irregular gray, sunken, necrotic spots ranging from 2 to 9 mm were observed on diseased leaves of T. terrestris landrace in Fushun County, Liaoning Province of northeast China in July 2021, with more than 32% of the plants being infected in a 18-ha field. The symptoms first appeared on older leaves and gradually spread to younger leaves. The lesions developed a white center gradually and became perforated; multiple lesions could coalesce (Fig. 1). Ten symptomatic leaves were collected and the diseased tissues were cut into small pieces, immersed in 1% NaOCl for 2 min, rinsed three times with sterile water, and placed on acidified potato dextrose agar (PDA) in Petri dishes at 25°C in darkness. Fifteen suspected Colletotrichum single-spore fungal isolates (JL1 to JL15) with consistent morphological characteristics were obtained, and isolate JL6 was selected for identification and pathogenicity testing. Colonies on PDA were flat with an entire margin, dense and white at first, then became dark gray with numerous black microsclerotia and formed a concentric circular pattern with aging. Conidia were single-celled, sickle-curved with a tapered tip and truncate base, ranging from 16.46 to 20.26 μm in length and 2.81 to 3.96 μm in width (n=100). Setae were dark brown, septate, straight with a slightly acute tip, 75.45 to 135.63×3.19 to 4.95 μm in size. Appressoria were dark brown, round or irregular, mostly in groups. All characteristics were consistent with the descriptions of C. truncatum (Damm et al. 2009). Further confirmation of the identification was determined according to methods described previously (Damm et al. 2009). The rDNA internal transcribed spacer region (OP364400, 585 bp), and actin (OP380867, 290 bp), beta-tubulin (OP380868, 498 bp), chitin synthase 1 (OP380869, 277 bp), glyceraldehyde-3-phosphate dehydrogenase (OP380870, 280 bp), and histone (OP380871, 411 bp) genes were amplified by PCR and sequenced (Carbone and Kohn 1999; Glass and& Donaldson 1995; Guerber et al. 2003; O'Donnell and Cigelnik 1997). BLAST results showed 98-100% similarity at 85-97% coverage compared to the corresponding sequences of the type strain CBS 151.35 (GU227862, GU227960, GU228156, GU228352, GU228254, and GU228058). Phylogenetic analysis combining all loci revealed that the isolate JL6 and the type strains of C. truncatum clustered in one group (Fig. 2). One-year-old healthy seedlings of T. terrestris (cultivar: landrace) were used for pathogenicity test. Suspension (1×105 conidia/mL) of isolate JL6 was sprayed on ten seedlings, and ten seedlings sprayed with sterilized distilled water were used as the control. Three replicates were performed on each treatment. All plants were kept at 28±1°C (12 h photoperiod), and were evaluated after 7 days. The inoculated plants showed lesions on the leaf surface, similar to those in the field, and the control remained symptomless. The pathogen was successfully reisolated and identified using the methods mentioned above. To our knowledge, this is the first report of C. truncatum causing anthracnose on T. terrestris, which will provide valuable information for designing strategies to manage anthracnose on T. terrestris.

Hypoxia, an important characteristic of bacterial biofilms, can hinder the generation of reactive oxygen species (ROS) in photodynamic therapy (PDT), leading to reduced therapeutic efficacy of PDT. In order to address this issue, fluorinated liposome was fabricated as an oxygen-sufficient nanoplatform for enhanced photodynamic eradication of bacterial biofilms. The liposomes (denoted as Lip-Ce6-PFH@O2) were prepared by co-encapsulation of O2 carrier perfluorohexane (PFH) and photosensitizer chlorin e6 (Ce6). Lip-Ce6-PFH@O2 could achieve efficient biofilm penetration due to the positively charged surface. The hypoxic microenvironment of biofilms would then be relieved, leading to the generation of more ROS under laser irradiation. Therefore, the bactericidal capability of PDT could be significantly improved because of the co-delivered O2 carrier PFH. Lip-Ce6-PFH@O2 exhibited much better antibiofilm ability than that of Lip-Ce6 both in vitro and in vivo. Meanwhile, Lip-Ce6-PFH@O2 also effectively alleviated inflammation symptoms and accelerated wound healing in the mice model. In general, this study provides a new paradigm to enhance the therapeutic efficacy of PDT for efficient biofilm eradication.

Tumor cell-induced platelet aggregation (TCIPA) is known as a critical step in hematogenous tumor metastasis. The endogenous nitric oxide (NO) plays an important role in anticoagulation, which might have great potential to inhibit TCIPA. Herein, a glutathione-sensitive supramolecular nanocarrier is prepared via host-guest interaction for effective delivery of NO and chemotherapeutic agent gemcitabine (GEM). NO could be effectively released in tumor cells and inhibits platelet activation and aggregation. The inhibition of TCIPA by NO could effectively attenuate the migration and invasion of tumor cells

Interfaces formed by correlated oxides offer a critical avenue for discovering emergent phenomena and quantum states. However, the fabrication of oxide interfaces with variable crystallographic orientations and strain states integrated along a film plane is extremely challenging by conventional layer-by-layer stacking or self-assembling. Here, the creation of morphotropic grain boundaries (GBs) in laterally interconnected cobaltite homostructures is reported. Single-crystalline substrates and suspended ultrathin freestanding membranes provide independent templates for coherent epitaxy and constraint on the growth orientation, resulting in seamless and atomically sharp GBs. Electronic states and magnetic behavior in hybrid structures are laterally modulated and isolated by GBs, enabling artificially engineered functionalities in the planar matrix. This work offers a simple and scalable method for fabricating unprecedented innovative interfaces through controlled synthesis routes as well as providing a platform for exploring potential applications in neuromorphics, solid-state batteries, and catalysis.

Pulmonary arterial hypertension (PAH) is a pulmonary vascular disease characterized by pulmonary vascular remodeling and right heart enlargement the pathogenesis of PAH is complicated; no biologic-based therapy is available for the treatment of PAH, but recent studies suggest that inflammatory response and abnormal proliferation of pulmonary artery smooth muscle cells are the main pathogenic mechanism, while the role of immune-related long non-coding RNAs (lncRNAs) remains unclear. The aim of this study was to systematically analyze immune-related lncRNAs in PAH. Here, we downloaded a publicly available microarray data from PAH and control patients (GSE113439). A total of 243 up-regulated and 203 down-regulated differentially expressed genes (DEGs) were screened, and immune-related DEGs were further obtained from ImmPort. The immune-related lncRNAs were obtained by co-expression analysis of immune-related mRNAs. Then, immune-related lncRNAs-mRNAs network including 2 lncRNAs and 6 mRNAs was constructed which share regulatory miRNAs and have significant correlation. Among the lncRNA-mRNA pairs, one pair (

Restenosis induced by neointimal hyperplasia is one of the key reasons limiting the long-term success of cardiovascular interventional therapy. However, it remains a serious challenge to completely overcome restenosis because of the dilemma of simultaneously activating human umbilical vein endothelial cells (HUVECs) and inhibiting human aortic smooth muscle cells (HASMCs). Herein, we developed a targeted nanomedicine encapsulating the liver X receptor (LXR) agonist, T0901317, for differentially regulating the behaviors of HUVECs and HASMCs. The stimulatory effect on HUVEC proliferation/migration and the inhibitory effect on HASMC proliferation/migration were confirmed

Surfaces with gradient topography are important in various fields but are difficult to fabricate. Herein, we report a facile and robust way to fabricate a surface with gradient topography of porous structure, in one direction, based on the breath figure (BF) method for the first time. The influencing factors including relative humidity (RH), sample immersion time, and solvent composition, affecting the speed, time, and model of the droplet growth, respectively, were investigated to control gradient BF pores with different ranges of pore sizes. Applying appropriate parameters, gradient BF pores with a diameter difference over 400% were prepared on one sample. The mechanism of gradient duration of solvent evaporation at different regions of a sample for fabricating gradient pores was proposed and experimentally verified with recording optical and thermographic changes of the sample in the BF procedure. This new method provides a novel site for gradient topography fabrication.

Pancreatic cancer is one of the most stroma-abundant solid cancers. Its desmoplastic nature restricts the penetration of drugs in tumor tissues and is considered as a major challenge for efficient chemotherapy. In the present study, we repurposed the use of captopril to deplete the overexpressed extracellular matrix (ECM) in stroma of pancreatic tumor. Precise delivery of captopril to cancer-associated fibroblasts (CAFs) was achieved using CAFs targeting peptide modified liposomes. The targeted delivery of captopril significantly downregulated the deposition of ECM by blocking the TGF-β1-Smad2 related signaling pathway, which improved the penetration of subsequently administrated liposome-encapsulated chemotherapeutic agent gemcitabine. It proved as a promising solution to break the aforementioned stromal barrier in pancreatic cancer therapy.

BACKGROUND Under the paradigm of Precision Medicine (PM), patients with the same disease can receive different personalized therapies according to their clinical and genetic features. These therapies are determined by the totality of all available clinical evidence, including results from case reports, clinical trials and systematic reviews. However, it is increasingly difficult for physicians to find such evidence from scientific publications, whose size is growing at an unprecedented pace. OBJECTIVE In this work, we propose the PM-Search system to facilitate the retrieval of clinical literature that contains critical evidence for or against giving specific therapies to certain cancer patients. METHODS The PM-Search system combines a Baseline Retriever that selects document candidates at large scale and an Evidence Re-ranker that finely reorders the candidates based on their evidence quality. The Baseline Retriever uses query expansion and keyword matching with the Elasticsearch retrieval engine, and the Evidence Re-ranker fits pre-trained language models to expert annotations that are derived from an active learning strategy. RESULTS The PM-Search system achieves the best performance in the retrieval of high-quality clinical evidence at the TREC PM Track 2020, outperforming the second-ranking systems by large margins (0.4780 v.s. 0.4238 for standard NDCG@30 and 0.4519 v.s. 0.4193 for exponential NDCG@30). CONCLUSIONS We present PM-Search, a state-of-the-art search engine to assist the practicing of evidence-based PM. PM-Search uses a novel BioBERT-based active learning strategy that models evidence quality and improves the model performance. Our analyses show that evidence quality is a distinct aspect from the general relevance, and specific modeling of evidence quality beyond general relevance is required for a PM search engine.

Weak tissue adhesion remains a major challenge in clinical translation of microneedle patches. Mimicking the structural features of honeybee stingers, stiff polymeric microneedles with unidirectionally backward-facing barbs were fabricated and embedded into various elastomer films to produce self-interlocking microneedle patches. The spirality of the barbing pattern was adjusted to increase interlocking efficiency. In addition, the micro-bleeding caused by microneedle puncturing adhered the porous surface of the patch substrate to the target tissue via coagulation. In the demonstrative application of myocardial infarction treatment, the bioinspired microneedle patches firmly fixed on challenging beating hearts, significantly reduced cardiac wall stress and strain in the infarct, and maintained left ventricular function and morphology. In addition, the microneedle patch was minimally invasively implanted onto beating porcine heart in 10 minutes, free of sutures and adhesives. Therefore, the honeybee stinger-inspired microneedles could provide an adaptive and convenient means to implant patches for various medical applications. STATEMENT OF SIGNIFICANCE: Adhesion between tissue and microneedle patches with smooth microneedles is usually weak. We introduce a novel barbing method of fabricating unidirectionally backward facing barbs with controllable spirality on the microneedles on microneedle patches. The microneedle patches self-interlock on mechanically dynamic beating hearts, similar to honeybee stingers. The micro-bleeding and coagulation on the porous surface provide additional adhesion force. The microneedle patches attenuate left ventricular remodeling via mechanical support and are compatible with minimally invasive implantation.

Oxidative therapy, which generates reactive oxygen species (ROS) via intracellular enzymatic reactions to achieve tumor ablation, is considered as an emerging approach to cancer treatment. Herein, nitric oxide (NO)-combined oxidative therapy is reported by integrating glutathione (GSH)-sensitive NO donor and pH-sensitive cinnamaldehyde (CA) prodrug into a mitochondria-targeted drug nanocarrier, which is prepared by the host-guest interaction between α-cyclodextrin (α-CD) and polyethylene glycol (PEG). After internalized by cancer cells, CA can be released in acidic endo/lysosome and finally induce ROS generation in mitochondria for oxidative therapy. At the same time, NO can be targeted delivered to mitochondria by a mitochondria-targeting strategy and then realize selective release of NO in mitochondria. NO can deplete intracellular predominant antioxidant GSH, which will enhance oxidative therapy of CA. Furthermore, peroxynitrite (ONOO

A polymer nanocomposite film decorated with highly dispersive nanoparticles was prepared by a liquid-liquid interface induced self-assembly method based on a breath figure process. The distribution as well as the orientation preference of the Janus particles within the polymer matrix could be dynamically controlled by adjusting the environmental conditions. Antibacterial and photocatalytic functionality was obtained for the nanocomposite films decorated with silver and titanium dioxide nanoparticles, respectively.

In this letter, light-responsive protein-encapsulated polyion complex (PIC) micelles were prepared by self-assembly of cationic block copolymer poly(N,N-dimethyl-N-(2-(methacryloyloxy)ethyl)-N-((2-nitrobenzyl)oxy)-2-oxoethanaminium bromide)-block-poly(carboxybetaine methacrylate) (PDMNBMA-b-PCBMA) and negatively charged bovine serum albumin (BSA). The PIC micelles were well characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). From the zeta potential measurement, the increase of the zeta potential of PIC micelles from ∼10 to ∼20 mV was observed when the solution pH decreased from 7.4 to 6.5, which could enhance the intracellular protein delivery efficiency. Moreover, the positively charged PDMNBMA blocks can be transformed to zwitterionic carboxybetaine units under UV irradiation, which could result in the disassembly of the PIC micelles. The release of BSA can therefore be drastically accelerated in the presence of UV irradiation. Meanwhile, the circular dichroism (C...

Pathologically elevated mechanical load promotes the adverse remodeling of left ventricle (LV) post myocardial infarction, which results in the progression from ischemic cardiomyopathy to heart failure. Cardiac patches could attenuate adverse LV remodeling by providing mechanical support to infarcted myocardium and border zone tissue. However, the mechanism of the translation from mechanical effects to favorable therapeutic outcome is still not clear. By transcriptome analysis, we found that the myocardial transcription levels of mechanosensitive ion channel proteins Piezo1 and Piezo2 significantly increased in patients with ischemic cardiomyopathy. In vitro tensile tests with local tissue information revealed a significant decrease in local strain and mechanical load in rat infarct. Cardiac function and geometry were preserved compared to non-treated control. Further, in LV myocardium of the patch-treated group, MI induced expression levels of Piezo1/2 were significantly reverted to the similar levels of the Sham group, indicating that cardiac patch beneficial effects were correlated with suppressing mechanosensitive genes, particularly Piezo1/2. These findings demonstrated the potential of cardiac patches in treating ICM patients with remodeling risks, and could provide guidance for improvement in next generation of patch devices.

The development of a controllable reactive nitrogen species (RNS) generation system for cancer treatment has remained elusive. Herein, a supramolecular prodrug nanoassemblies (SPNA) strategy that co-delivers a nitric oxide (NO) donor and a superoxide anion (O2•-) inducing chemotherapeutic agent was reported for RNS-potentiated chemotherapy. The mole ratio of platinum(IV) prodrug and NO donor could be precisely tailored in SPNAPt/NO. Platinum(II) and NO would be released intracellularly to produce a highly toxic RNS, peroxynitrite anion (ONOO-). The levels of glutathione reductase (GR) and xeroderma pigmentosum group A (XPA) were down-regulated by ONOO-, thus synergistically decreasing detoxification and blocking DNA damage repair of Pt-based chemotherapy. The RNS-potentiated efficacy of SPNAPt/NO was validated on subcutaneous hepatoma xenograft models and an orthotopic cisplatin-resistant hepatoma model. This co-delivery strategy of NO donor and O2•- inducing chemotherapeutic agents for RNS-mediated therapy provides an insightful direction for cancer treatment.

Ocular infection induced by bacteria and fungi is a major cause of visual impairment and blindness. Topical administration of antibiotics remains the first-line treatment, as effective eradication of pathogens is the core of the anti-infection strategy. Whereas, eye drops lack efficiency and have relatively low bioavailability. Intraocular injection may cause concurrent ocular damage and secondary infection. In addition, antibiotic-based management can be limited by the low sensitivity to multidrug-resistant bacteria. Nanomedicine is proposed as a prospective, effective, and noninvasive platform to mediate ocular delivery and combat pathogen or even resistant strains. Nanomedicine can not only carry antimicrobial agents to fight against pathogens but also directly active microbicidal capability, killing pathogens. More importantly, by modification, nanomedicine can achieve enhanced residence time and release time on the cornea, and easy penetration through corneal tissues into anterior and posterior segments of the eye, thus improving the therapeutic effect for ocular infection. In this review, several categories of antimicrobial nanomedicine are systematically discussed, where the efficiency and possibility of further embellishment and improvement to adapt to clinical use are also investigated. All in all, novel antimicrobial nanomedicine provides potent and prospective ways to manage severe and refractory ocular infections.

The sandwich structures are three- or multilayered structures such that their mechanical properties are better than each single layer. In the current research, a three-layered cylindrical shell including a functionally graded porous core and two reinforced nanocomposite face sheets resting on the Pasternak foundation is used as model to provide a comprehensive understanding of vibrational behavior of such structures. The core is made of limestone, while the epoxy is utilized as the top and bottom layers’ matrix phase and also it is reinforced by the graphene nanoplatelets (GNPs). The pattern of the GNPs dispersion and the pores distribution play a crucial role at the continuous change of the layers’ properties. The sinusoidal shear deformation shells theory and the Hamilton’s principle are employed to derive the equations of motion for the mentioned cylindrical sandwich shell. Ultimately, the impacts of the model’s geometry, foundation moduli, mode number, and deviatory radius on the vibrational behavior are investigated and discussed. It is revealed that the natural frequency and rotation angle of the sandwich shell are directly related. Moreover, mid-radius to thickness ratio enhancement results in the natural frequency reduction. The results of this study can be helpful for the future investigations in such a broad context. Furthermore, for the pipe factories current study can be effective at their designing procedure.

Pandemics caused by viruses have resulted in incalculable losses to human beings, which are exacerbated due to the lack of antiviral drugs. Sulfonic group modified nanomedicine has been proved to possess a broad-spectrum antiviral ability. However, it is very challenging to maintain the antiviral activity in a high protein environment in vivo. To improve the tolerance to the complex biological environment, sulfonic mixed-charge modified gold nanoparticles (MC_AuNPs) were prepared in this research by introducing positively charged ligands into sulfonic ligand modified gold nanoparticles. The MC_AuNPs showed excellent non-fouling ability while retaining comparable antiviral ability to single sulfonic ligand modified gold nanoparticles (MDS_AuNPs). The MC_AuNPs maintained their antiviral ability in 10 mg mL−1 protein solutions, but the MDS_AuNPs completely lost their antiviral capability in 1 mg mL−1 protein medium. The mixed-charge modification strategy provides a practical avenue to maintain the antiviral capability of HSPG mimicking nanoparticles in high protein environments.

Atherosclerosis is the leading global cause of mortality. The occurrence of coronary artery disease (CAD) is regulated by a diversity of pathways, including circRNAs. However, the potential mechanisms of circRNAs in CAD remain unclear. Here, qRT-PCR was used to examine the expressions of miR-149 and circ_ROBO2. Their influences on cell proliferation, migration, and apoptosis were measured by CCK-8, trans­well, and flow cytometry assays, respectively. The protein levels of p-IκBα and NF-κB p65 were examined using western blot. The molecular interactions were validated using dual luciferase reporter and RNA pull-down assays. The expression patterns of circ_ROBO2 and miR-149 in CAD patients and PDGF-BB-treated human aortic smooth muscle cells (HASMCs) were upregulated and downregulated, respectively. Knockdown of circ_ROBO2 could markedly inhibit the capabilities of proliferation and migration, enhance the apoptotic rate, and suppress NF-κB signaling in PDGF-BB-treated HASMCs. Mechanistically, circ_ROBO2 acted as a sponge of miR-149 to activate TRAF6/NF-κB signaling. Rescue studies demonstrated that neither silencing miR-149 nor activation of NF-κB signaling obviously abolished the biological roles of circ_ROBO2 knockdown in PDGF-BB treated-HASMCs. This discovery elucidated a functional mechanism of circ_ROBO2 in CAD, suggesting that circRNAs serve a vital role in the progression of CAD.

The cornea provides important protection for human eyes from invasion of alien substances. However, its blockage on the infiltration of molecules also constitutes a great challenge for noninvasive trans-cornea delivery of drugs. Here we report polyamino acid-based S-nitrosothiols with high cationic charge density as a NO carrier to overcome cornea associated blockage in ophthalmological therapy. Our results demonstrate that the cationic nature of the polymer promoted transcytosis, which greatly enhances the trans-cornea delivery of the NO donor and bypasses cornea barriers on passive drug diffusion. The combination of super cation and glutathione responsiveness synergistically enhanced intraocular delivery of topically administered poly(2-acetamido-N-triethylenetetramine-3-nitrosothiol-3-methylbutanamide)aspartamide, effectively alleviating high intraocular pressure in mice with glaucoma. Such a noninvasive "barrier hopping" approach not only serves as an inspiration in improving the efficiency of trans-cornea drug delivery but also has great potential in overcoming drug transporting barriers in other biomedical applications.

The development of antibiotics resistance has made multidrug-resistant (MDR) bacterial infection one of the most serious global health issues. Photothermal therapy (PTT) is an emerging therapeutic mode which can be applied to bacterial infection without inducing resistance. Moreover, enhanced therapeutic efficacy and less tissue damage can be realized with NIR-II fluorescence imaging (FLI) guided PTT. Herein, a polymeric luminogen with aggregation-induced emission (AIEgens) characteristics, poly(dithieno[3,2-b:2',3'-d]pyrrole-benzo[1,2-c:4,5-c']bis([1,2,5]thiadiazole)) (PDTPTBT), was synthesized and used as a photothermal agent for PTT of bacterial infections. PDTPTBT was encapsulated into liposomes (L-PDTPTBT) for improved water dispersibility. Upon 808 nm NIR irradiation, L-PDTPTBT can eliminate multiple bacteria including the Gram-positive methicillin-resistant Staphylococcus aureus and Enterococcus faecalis, the Gram-negative Escherichia coli and Pseudomonas aeruginosa. Serious damage of bacterial membrane and leakage of cytoplasm is observed after photothermal treatment using L-PDTPTBT. The potential of the formulation has been demonstrated in two infected animal models: (i) a subcutaneous abscess model and (ii) a diabetic skin infection model. In the diabetic skin infection model, the death of mice is largely suppressed and the wounds can heal more quickly with treatment of L-PDTPTBT under NIR irradiation. The excellent photothermal bactericidal ability and low cytotoxicity make L-PDTPTBT potential candidate for treating MDR bacterial infections in the future.

The continuously increasing bacterial resistance has become a big threat to public health worldwide, which makes it urgent to develop innovative antibacterial strategies. Nanotechnology-based drug delivery systems are considered as promising strategies in combating bacterial infections which are expected to improve the therapeutic efficacy and minimize the side effects. Unfortunately, the conventional nanodrug delivery systems always suffer from practical dilemmas, including incomplete and slow drug release, insufficient accumulation in infected sites, and weak biofilm penetration ability. Stimuli-responsive nanoplatforms are hence developed to overcome the disadvantages of conventional nanoparticles. In this review, we provide an extensive review of the recent progress of endogenous and exogenous stimuli-responsive nanoplatforms in the antibacterial area, including planktonic bacteria, intracellular bacteria, and bacterial biofilms. Taking advantage of the specific infected microenvironment (pH, enzyme, redox, and toxin), the mechanisms and strategies of the design of endogenous stimuli-responsive nanoplatforms are discussed, with an emphasis on how to improve the therapeutic efficacy and minimize side effects. How to realize controlled drug delivery using exogenous stimuli-responsive nanoplatforms especially light-responsive nanoparticles for improved antibacterial effects is another topic of this review. We especially highlight photothermal-triggered drug delivery systems by the combination of photothermal agents and thermo-responsive materials. This article is categorized under: Therapeutic Approaches and Drug DiscoveryNanomedicine for Infectious Disease Therapeutic Approaches and Drug DiscoveryEmerging Technologies.

The fabrication of Gemcitabine (GEM) prodrug was reported to be an effective method to enhance its pancreatic cancer treatment efficiency. Here, a kind of nanocarbon-based materials, nanodiamond (ND), was selected as the nanocarrier of GEM, owing to its outstanding surface properties and non-cytotoxicity. The polyelectrolytes, polyethyleneimine and polyacrylic acid, were used to self-assemble outside ND surface through electrostatic forces, followed by attachment of polyethylene glycol to address better biocompatibility. GEM was conjugated with an enzyme-sensitive peptide gly-phe-leu-gly to build up the controlled release platform. From characterization results of dynamic laser scattering, zeta potential and transmission electron microscope, the significant improvement of ND stability in physiological condition was proved. Non-cytotoxicity of this functionalized ND carriers and cytotoxicity of the prodrug against BxPC-3 pancreatic cancer cells were indicated by methylthiazolyl tetrazolium (MTT) assay. In vivo experiments also revealed its superior anticancer effect compared with free GEM treatment. Therefore, the combination of polymer coated NDs with high surface capability and enzyme-responsive intracellular GEM release make it possible to realize higher treatment efficiency on pancreatic tumor therapy.

Autophagy triggered by reactive oxygen species (ROS) in photodynamic therapy (PDT) generally exhibits an anti-apoptotic effect to promote cell survival. Herein, an innovative supramolecular nanoplatform was fabricated for enhanced PDT by converting the role of autophagy from pro-survival to pro-death. The respiration inhibitor 3-bromopyruvate (3BP), which can act as an autophagy promoter and hypoxia ameliorator, was integrated into photosensitizer chlorin e6 (Ce6)-encapsulated nanoparticles to combat hypoxic tumor. 3BP could inhibit respiration by down-regulating HK-II and GAPDH expression to significantly reduce intracellular oxygen consumption rate, which could relieve tumor hypoxia for enhanced photodynamic cancer therapy. More importantly, the autophagy level was significantly elevated by the combination of 3BP and PDT determined by Western blot, immunofluorescent imaging, and transmission electron microscopy. It was very surprising that excessively activated autophagy promoted cell apoptosis, leading to the changeover of autophagy from pro-survival to pro-death. Therefore, PDT combined with 3BP could achieve efficient cell proliferation inhibition and tumor regression. Furthermore, hypoxia-inducible factor-1α (HIF-1α) could be down-regulated after tumor hypoxia was relieved by 3BP. Tumor metastasis could then be effectively inhibited by eliminating primary tumors and down-regulating HIF-1α expression. These results provide an inspiration for future innovative approaches of cancer therapy by triggering pro-death autophagy.

Anthocyanins are a type of natural pigment that have high potential for development and utilization in regions like food, pharmaceutical, and cosmetic industries, with nitrogen and phosphorus starvation possibly promoting their accumulation in grapes. However, it remains unclear whether such starvation impacts the grape callus, or how the co-starvation of nitrogen and phosphorus affects the biosynthesis of anthocyanins. Here, we investigated how nitrogen starvation, phosphorus starvation, and the co-starvation of these two elements affects the synthesis of anthocyanins in the callus of grape skin. Results showed that separate starvation of nitrogen and phosphorus, as well as nitrogen and phosphorus co-starvation, inhibited callus growth, while significantly promoting the accumulation of anthocyanins. However, co-starvation did not facilitate anthocyanin biosynthesis during the later stages of callus growth. qRT-PCR analysis showed that the expression of VvUFGT and VvMYBA1 was closely related to anthocyanin accumulation in the callus under nitrogen and phosphorus starvation. Besides, we also confirmed that the abscisic acid signaling pathway was involved in anthocyanin accumulation as well as callus resistance under adverse conditions. This study provides a basis for investigating the regulatory mechanisms of anthocyanin synthesis in grapes, as well as theoretical support for the production of anthocyanins by callus culture. Even though nitrogen and phosphorus deficiencies have been reported to promote anthocyanin biosynthesis in grapevine berries, whether the same deficiencies also induce anthocyanin accumulation in grape callus and whether nitrogen and phosphorus co-deficiency enhances this induction have yet to be reported. Therefore, the present study to investigate the effects of nitrogen starvation, phosphorus starvation, and nitrogen and phosphorus co-starvation on anthocyanin accumulation and ABA signaling in grape callus.

A novel atmospheric pressure ionization mass spectrometry based on wire desorption and electrospray ionization (WD-ESI) for direct analysis was developed to characterize chemical compounds with different polarities and thermal stabilities at atmospheric pressure. This technique is a variant of the thermal desorption electrospray ion source developed by Shiea et al. One large improvement is that the heating speed (>500 °C/s) of the thermal desorption in this work is extremely fast, using a self-heating metal wire, with which sample solution can splash from the surface to form small droplets and thus the analytes can be protected from thermal decomposition. With this feature, we have successfully achieved soft ionization of highly polar organic and biological compounds such as aflatoxin, small peptides, and even large proteins from complex matrices. The simple structure and self-cleaning capability of the WD-ESI source make it ideal for on-site screening in various applications such as food safety and biodrug testing, especially when coupled with a transportable mass spectrometer.

Antibiotic resistance is an increasingly serious threat to global public health, which can lead to the decrease of the effectiveness of antibiotics. The combination therapy of antibiotic and mild temperature photothermal therapy (PTT) is adopted to address this issue in this work. An antibiotic-loaded nanoplatform is fabricated based on two-dimensional (2D) molybdenum disulfide (MoS2) nanoflakes as effective near-infrared (NIR) photothermal agent. The MoS2 nanoflakes is modified with positively charged quaternized chitosan (QCS) to improve the dispersion stability and enhance the interaction between MoS2 nanoflakes and bacterial membrane. The QCS modified MoS2 nanoflakes (QCS-MoS2) is expected to adhere onto the membrane of methicillin-resistant Staphylococcus aureus (MRSA) and depolarize the bacterial membrane by local hyperthermia under NIR irradiation. A first-line antibiotic, ofloxacin (OFLX), can be loaded onto QCS-MoS2 by π-π stacking and hydrophobic interaction. Due to the combined antibiotic-photothermal therapy, superior bactericidal ability was achieved at mild temperature (45 °C) and low antibiotic concentration. Such synergistic mild-temperature photothermal/antibiotic therapy can not only avoid the damage to neighboring tissue by PTT, but also reduce the development of drug resistance, providing an innovative way for the treatment of bacterial infections.

The size of the nanocarrier is considered one of the most important issues for its therapeutic effect. Thus, an intelligent nanocarrier with dynamic size has been explored as a promising approach to fulfill the requirements for both efficient accumulation according to the enhanced penetration and retention (EPR) effect and deep penetration into tumor tissue. Herein, structure-switchable triplex DNA was modified on gold nanoparticles (AuNPs) to investigate its potential to modulate the nanoparticle dynamic disassembly process among the tumor microenvironment. We report that the pH-sensitive triplex DNA exhibited outstanding sensitivity and size tunability in triggering the disassembly of AuNP clusters into smaller sizes among the tumor acidic environment, leading to better permeability both in vitro and in vivo. By further combination of the telomerase-sensitive hairpin DNA loaded with chemotherapy drug doxorubicin (DOX), a cancer-specific intracellular drug-release function was also realized, resulting in a precise treatment effect and lower toxicity on normal cells. Through comodification of these two structure-switchable DNA chains on AuNPs and construction of nanoparticle assemblies with proper size, programmed disassembly and drug-release function in tissue and cell level, respectively, were successfully combined and eventually facilitated a highly efficient nanodrug transportation process, from tumor accumulation to deep penetration and precise cancer chemotherapy. The study provided the prospect of utilizing functionalized DNA in optimization of nanocarrier delivery efficiency.

Supramolecular nanomaterials as drug carriers have recently received increasing attention due to their intrinsic merits such as high stability, strong inclusion capability, and facile modification of the parental structure; however, intelligent ones with combined capacities of long blood circulation, highly efficient tumor cell uptake, and site-oriented drug release inside tumor cells are still rather limited. Herein, we report a strategy using supramolecular aggregation-induced emission (AIE) nanodots for image-guided drug delivery, which integrate both the advantages of AIE and supramolecular nanomaterials. The supramolecular AIE dots are prepared by the host-guest coassembly of the matrix metalloproteinase-2 (MMP-2) sensitive PEG-peptide (PEG2000-RRRRRRRR (R8)-PLGLAG-EKEKEKEKEKEK (EK6)) and functional α-cyclodextrins (α-CD) derivatives that are conjugated with the anticancer drug gemcitabine (GEM) and a far-red/near-infrared fluorescent rhodanine-3-acetic acid-based AIE luminogen, respectively. The supramolecular AIE dots realize long blood circulation time by virtue of the zwitterionic stealth peptide EK6. After largely accumulating in tumor tissues by the enhanced permeability and retention effect, the supramolecular AIE dots can successively respond to the tumor-overexpressed MMP-2 and intracellular reductive microenvironment, achieving both enhanced cancer cellular uptake and selective GEM release within cancer cells, which thus exhibit excellent tumor inhibition ability in both subcutaneous and orthotopic pancreatic tumor models.