Overexpression of SlWRKY6 enhances drought tolerance by strengthening antioxidant defense and stomatal closure via ABA signaling in Solanum lycopersicum L.

Drought is a major handicap for plant growth and development. WRKY proteins comprise one of the largest families of plant transcription factors, playing important roles in plant growth and stress tolerance. In tomato (Solanum lycopersicum L.), different WRKY transcription factors differentially (positively or negatively) regulate drought tolerance, however, the role of SlWRKY6 in drought response and the associated molecular mechanisms of stress tolerance remain unclear. Here we report that SlWRKY6, a member of the WRKYII-b group, is involved in the functional aspects of drought resistance in tomato. Transcriptional activation assays show that SlWRKY6 is transcriptionally active in yeast cells, while the subcellular localization assay indicates that SlWRKY6 is localized in the nucleus. Overexpression of SlWRKY6 in tomato plants resulted in stronger antioxidant capacity and drought resistance as manifested by increased photosynthetic capacity and decreased reactive oxygen species accumulation, malondialdehyde content and relative electrolyte leakage in transgenic tomato plants compared with wild-type under drought stress. Moreover, increased abscisic acid (ABA) content and transcript abundance of ABA synthesis and signaling genes (NCED1, NCED4, PYL4, AREB1 and SnRK2.6) in the transgenic tomato plants indicated potential involvement of the ABA pathway in SlWRKY6-induced drought resistance in tomato plants. Inspection of 2-kb sequences upstream of the predicted binding sites in the promoter of SlNCED1/4 identified two copies of the core W-box (TTGACC/T) sequence in the promoter of SlNCED1/4, which correlates well with the expression of these genes in response to drought, further suggesting the involvement of ABA-dependent pathway in SlWRKY6-induced drought resistance. The study unveils a critical role of SlWRKY6, which can be useful to further reveal the drought tolerance mechanism and breeding of drought-resistant tomato varieties for sustainable vegetable production in the era of climate change.

NIR-II fluorescence and PA imaging guided activation of STING pathway in photothermal therapy for boosting cancer immunotherapy by theranostic thermosensitive liposomes.

Photothermal immunotherapy has shown great potential for efficient cancer treatment. However, the immunosuppressive tumor microenvironment forms a heavy barrier for photothermal-induced anti-tumor immunity by inhibiting dendritic cell (DC) maturation and cytotoxic T cell response. Moreover, the lack of reliable spatiotemporal imaging modalities makes photothermal immunotherapy difficult to guide tumor ablation and monitor therapeutic outcomes in real time. Herein, we designed a theranostic thermosensitive liposome (PLDD) as a versatile nanoplatform to boost the adaptive anti-tumor immunity of photothermal immunotherapy and to achieve multiple bioimaging modalities in a real-time manner. PLDD contains two major functional components: a multifunctional photothermal agent (DTTB) and an immune potentiator STING pathway agonist (DMXAA). Upon irradiation, the heat generated by DTTB induced the immunogenic cell death (ICD) of the tumor and dissociated the structure of thermosensitive liposome to release DMXAA, which ultimately activated the STING pathway and promoted the ICD-induced immune response by increasing DC cell maturation and T cell recruitment. Moreover, the DTTB in PLDD displayed excellent second near-infrared (NIR-II) fluorescence and photoacoustic (PA) dual-modal imaging, which provided omnibearing information on the tumor and guided the subsequent therapeutic operation. Therefore, this versatile PLDD with light-triggered promotion of anti-tumor immunity and multiple spatiotemporal imaging profiles holds great potential for the future development of cancer immunotherapy.

Targeting the activity of T cells by membrane surface redox regulation for cancer theranostics.

T cells play a determining role in the immunomodulation and prognostic evaluation of cancer treatments relying on immune activation. While specific biomarkers determine the population and distribution of T cells in tumours, the in situ activity of T cells is less studied. Here we designed T-cell-targeting fusogenic liposomes to regulate and quantify the activity of T cells by exploiting their surface redox status as a chemical target. The T-cell-targeting fusogenic liposomes equipped with 2,2,6,6-tetramethylpiperidine (TEMP) groups neutralize reactive oxygen species protecting T cells from oxidation-induced loss of activity. Meanwhile, the production of paramagnetic 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) radicals allows magnetic resonance imaging quantification of the T cell activity. In multiple mouse models, the T-cell-targeting fusogenic liposomes led to efficient tumour inhibition and to early prediction of radiotherapy outcomes. This study uses a chemical targeting strategy to measure the in situ activity of T cells for cancer theranostics and may provide further understanding on engineering T cells for cancer treatment.

Identifying a 6-Gene Prognostic Signature for Lung Adenocarcinoma Based on Copy Number Variation and Gene Expression Data.

The occurrence of lung adenocarcinoma (LUAD) is a complicated process, involving the genetic and epigenetic changes of proto-oncogenes and oncogenes. The objective of this study was to establish new predictive signatures of lung adenocarcinoma based on copy number variations (CNVs) and gene expression data. Next-generation sequencing was implemented to obtain gene expression and CNV information. According to univariate, multivariate survival Cox regression analysis, and LASSO analysis, the expression profiles of lung adenocarcinoma patients were screened and a risk score formula was established and experimentally validated in a local cohort. The model was evaluated by three independent cohorts (TCGA-LUAD, GSE31210, and GSE30219), and then validated by clinical samples from LUAD patients. A total of 844 CNV-related differentially expressed genes (CNV-related DEGs) were identified. These genes are significantly associated with the imbalance of various oxidative stress pathways. A CNV-associated-six gene signature was dramatically linked to overall survival in lung adenocarcinoma samples from both training and validation groups. Functional enrichment analysis further revealed involvement of genes in p53 signaling pathway and cell cycle as well as the mismatch repair pathway. Risk score is an independent marker considering clinical parameters and had better prediction in clinical subpopulation. The same signature also classified tumor tissues of clinical patients with CNV detected from their corresponding nontumorous tissues with an accuracy of 0.92. In conclusion, we identified a new class of 6 CNV-related gene markers that may act as efficient prognostic predictors of lung adenocarcinoma, thus contributing to individualized treatment decisions in patients.

Increased ACS Enzyme Dosage Causes Initiation of Climacteric Ethylene Production in Tomato.

Fruits of wild tomato species show different ethylene-dependent ripening characteristics, such as variations in fruit color and whether they exhibit a climacteric or nonclimacteric ripening transition. 1-Aminocyclopropane-1-carboxylic acid (ACC) synthase (ACS) and ACC oxidase (ACO) are key enzymes in the ethylene biosynthetic pathway encoded by multigene families. Gene duplication is a primary driver of plant diversification and angiosperm evolution. Here, interspecific variations in the molecular regulation of ethylene biosynthesis and perception during fruit ripening in domesticated and wild tomatoes were investigated. Results showed that the activated ACS genes were increased in number in red-ripe tomato fruits than in green-ripe tomato fruits; therefore, elevated dosage of ACS enzyme promoted ripening ethylene production. Results showed that the expression of three ACS isogenes ACS1A, ACS2, and ACS4, which are involved in autocatalytic ethylene production, was higher in red-ripe tomato fruits than in green-ripe tomato fruits. Elevated ACS enzyme dosage promoted ethylene production, which corresponded to the climacteric response of red-ripe tomato fruits. The data suggest that autoinhibitory ethylene production is common to all tomato species, while autocatalytic ethylene production is specific to red-ripe species. The essential regulators Non-ripening (NOR) and Ripening-Inhibitor (RIN) have experienced gene activation and overlapped with increasing ACS enzyme dosage. These complex levels of transcript regulation link higher ethylene production with spatiotemporal modulation of gene expression in red-ripe tomato species. Taken together, this study shows that bursts in ethylene production that accompany fruit color changes in red-ripe tomatoes are likely to be an evolutionary adaptation for seed dispersal.

Navigations of the targeting pathway of nanomedicines toward tumor.

INTRODUCTION: Nanomedicines (NMs) have emerged as a promising approach for revolutionizing cancer treatment outcomes, mainly due to their benefits in the tumor-targeted delivery of therapeutics. The preferential accumulation of NMs in tumors has been widely verified by macroscopical technologies. Accordingly, several classic and emerging targeting mechanisms have been proposed to support the tumor-specific delivery of NMs. The targeting mechanism has been a topic of intense interest and controversy in the field of NMs development. Especially, the mechanisms by which NMs target tumor remain elusive. AREA COVERED: This topical review mainly discussed the evolution of the targeting mechanisms, crucial issues associated with each mechanism, and confused debates among the mechanisms. The targeting mechanisms of tumor-specific NMs discussed here include the enhanced permeability and retention (EPR) effect, protein corona-mediated targeting delivery, circulating cell mediated transportation, and transcytosis. EXPERT OPINION: It is of great significance for ultimate clinical translation to have more comprehensive considerations on the mechanism driving the pathway of NMs toward tumors. Our thoughts in this review are expected to provide a comprehensive understanding of the mechanisms and elicit thorough explorations of new mechanisms to renovate the knowledge framework of NMs delivery. [Figure: see text].

Comparison of the Response to the CXCR4 Antagonist AMD3100 during the Development of Retinal Organoids Derived from ES Cells and Zebrafish Retina.

Retinal organoids generated from human embryonic stem cells or iPSCs recreate the key structural and functional features of mammalian retinal tissue in vitro. However, the differences in the development of retinal organoids and normal retina in vivo are not well defined. Thus, in the present study, we analyzed the development of retinal organoids and zebrafish retina after inhibition of CXCR4, a key role in neurogenesis and optic nerve development, with the antagonist AMD3100. Our data indicated that CXCR4 was mainly expressed in ganglion cells in retinal organoids and was rarely expressed in amacrine or photoreceptor cells. AMD3100 treatment reduced the retinal organoid generation ratio, impaired differentiation, and induced morphological changes. Ganglion cells, amacrine cells, and photoreceptors were decreased and abnormal locations were observed in organoids treated with AMD3100. Neuronal axon outgrowth was also damaged in retinal organoids. Similarly, a decrease of ganglion cells, amacrine cells, and photoreceptors and the distribution of neural outgrowth was induced by AMD3100 treatment in zebrafish retina. However, abnormal photoreceptor ensembles induced by AMD3100 treatment in the organoids were not detected in zebrafish retina. Therefore, our study suggests that although retinal organoids might provide a reliable model for reproducing a retinal developmental model, there is a difference between the organoids and the retina in vivo.

Osteopontin targeted theranostic nanoprobes for laser-induced synergistic regression of vulnerable atherosclerotic plaques.

Vulnerable atherosclerotic plaque (VASPs) is the major pathological cause of acute cardiovascular event. Early detection and precise intervention of VASP hold great clinical significance, yet remain a major challenge. Photodynamic therapy (PDT) realizes potent ablation efficacy under precise manipulation of laser irradiation. In this study, we constructed theranostic nanoprobes (NPs), which could precisely regress VASPs through a cascade of synergistic events triggered by local irradiation of lasers under the guidance of fluorescence/MR imaging. The NPs were formulated from human serum albumin (HSA) conjugated with a high affinity-peptide targeting osteopontin (OPN) and encapsulated with photosensitizer IR780 and hypoxia-activatable tirapazamine (TPZ). After intravenous injection into atherosclerotic mice, the OPN-targeted NPs demonstrated high specific accumulation in VASPs due to the overexpression of OPN in activated foamy macrophages in the carotid artery. Under the visible guidance of fluorescence and MR dual-model imaging, the precise near-infrared (NIR) laser irradiation generated massive reactive oxygen species (ROS), which resulted in efficient plaque ablation and amplified hypoxia within VASPs. In response to the elevated hypoxia, the initially inactive TPZ was successively boosted to present potent biological suppression of foamy macrophages. After therapeutic administration of the NPs for 2 weeks, the plaque area and the degree of carotid artery stenosis were markedly reduced. Furthermore, the formulated NPs displayed excellent biocompatibility. In conclusion, the developed HSA-based NPs demonstrated appreciable specific identification ability of VASPs and realized precise synergistic regression of atherosclerosis.

Bioimaging guided pharmaceutical evaluations of nanomedicines for clinical translations.

Nanomedicines (NMs) have emerged as an efficient approach for developing novel treatment strategies against a variety of diseases. Over the past few decades, NM formulations have received great attention, and a large number of studies have been performed in this field. Despite this, only about 60 nano-formulations have received industrial acceptance and are currently available for clinical use. Their in vivo pharmaceutical behavior is considered one of the main challenges and hurdles for the effective clinical translation of NMs, because it is difficult to monitor the pharmaceutic fate of NMs in the biological environment using conventional pharmaceutical evaluations. In this context, non-invasive imaging modalities offer attractive solutions, providing the direct monitoring and quantification of the pharmacokinetic and pharmacodynamic behavior of labeled NMs in a real-time manner. Imaging evaluations have great potential for revealing the relationship between the physicochemical properties of NMs and their pharmaceutical profiles in living subjects. In this review, we introduced imaging techniques that can be used for in vivo NM evaluations. We also provided an overview of various studies on the influence of key parameters on the in vivo pharmaceutical behavior of NMs that had been visualized in a non-invasive and real-time manner.

m6A-Maize: Weakly supervised prediction of m6A-carrying transcripts and m6A-affecting mutations in maize (Zea mays).

With the rapid development of high-throughput sequencing techniques nowadays, extensive attention has been paid to epitranscriptomics, which covers more than 150 distinct chemical modifications to date. Among that, N6-methyladenosine (m6A) modification has the most abundant existence, and it is also significantly related to varieties of biological processes. Meanwhile, maize is the most important food crop and cultivated throughout the world. Therefore, the study of m6A modification in maize has both economic and academic value. In this research, we proposed a weakly supervised learning model to predict the situation of m6A modification in maize. The proposed model learns from low-resolution epitranscriptome datasets (e.g., MeRIP-seq), which predicts the m6A methylation status of given fragments or regions. By taking advantage of our prediction model, we further identified traits-associated SNPs that may affect (add or remove) m6A modifications in maize, which may provide potential regulatory mechanisms at epitranscriptome layer. Additionally, a centralized online-platform was developed for m6A study in maize, which contains 58,838 experimentally validated maize m6A-containing regions including training and testing datasets, and a database for 2,578 predicted traits-associated m6A-affecting maize mutations. Furthermore, the online web server based on proposed weakly supervised model is available for predicting putative m6A sites from user-uploaded maize sequences, as well as accessing the epitranscriptome impact of user-interested maize SNPs on m6A modification. In all, our work provided a useful resource for the study of m6A RNA methylation in maize species. It is freely accessible at www.xjtlu.edu.cn/biologicalsciences/maize.

Comparative Physiological and Proteomic Analyses Reveal the Mechanisms of Brassinolide-Mediated Tolerance to Calcium Nitrate Stress in Tomato.

Secondary salinization caused by the overaccumulation of calcium nitrate [Ca(NO3)2] in soils due to excessive fertilization has become one of the major handicaps of protected vegetable production. Brassinolide, a bioactive plant steroid hormone, plays an important role in improving abiotic stress tolerance in plants. However, whether and how brassinolide (BR) can alleviate Ca(NO3)2 stress remains elusive. Here, we investigated the effects of exogenous BR on hydroponically grown tomato (Solanum lycopersicum L.) plants under Ca(NO3)2 stress through proteomics combined with physiological studies. Proteomics analysis revealed that Ca(NO3)2 stress affected the accumulation of proteins involved in photosynthesis, stress responses, and antioxidant defense, however, exogenous BR increased the accumulation of proteins involved in chlorophyll metabolism and altered the osmotic stress responses in tomatoes under Ca(NO3)2 stress. Further physiological studies supported the results of proteomics and showed that the exogenous BR-induced alleviation of Ca(NO3)2 stress was associated with the improvement of photosynthetic efficiency, levels of soluble sugars and proteins, chlorophyll contents, and antioxidant enzyme activities, leading to the reduction in the levels of reactive oxygen species and membrane lipid peroxidation, and promotion of the recovery of photosynthetic performance, energy metabolism, and plant growth under Ca(NO3)2 stress. These results show the importance of applying BR in protected agriculture as a means for the effective management of secondary salinization.

Comparative transcriptomic and metabolomic analyses reveal the protective effects of silicon against low phosphorus stress in tomato plants.

Phosphorus (P) is an essential nutrient controlling plant growth and development through the regulation of basic metabolic processes. Soil P deficiency is one of the major limiting factors for sustainable crop production worldwide. Previous studies have demonstrated that silicon (Si), as a beneficial element, promotes plant nutrition, growth, development, and responses to low P (LP) stress; however, the molecular mechanisms underlying Si-mediated LP tolerance remain largely unclear. Here, we found that LP + Si treatment increased the net photosynthetic rate and shoot fresh weight by 34.3%, and 121.3%, respectively compared with LP alone. RNA-sequencing and metabolomic analyses were subsequently performed with tomato plants grown under control and P depleted conditions with or without Si amendment. RNA-sequencing showed that Si supply alters not only the expression of genes involved in the metabolism of carbon (C), nitrogen (N), and P but also phosphorylation processes and metabolism of glutathione and reactive active oxygen in tomato roots. Si also affected the expression of genes encoding major transcription factors such as WRKY and MYB under LP stress. Moreover, a set of genes encoding the enzymes or regulators of organic acid (OA) metabolism or secretion were differentially expressed in Si-treated P deficient roots compared with those in LP stress alone. Furthermore, the metabolomic analysis showed that the levels of several OAs were significantly elevated in Si-treated P deficient roots. Taken together, these results indicate that exogenous Si increases the secretion of OAs by modulating C/N metabolism in LP-treated tomato roots and thereby improving plant growth under LP stress.

Exploiting the acquired vulnerability of cisplatin-resistant tumors with a hypoxia-amplifying DNA repair-inhibiting (HYDRI) nanomedicine.

Various cancers treated with cisplatin almost invariably develop drug resistance that is frequently caused by substantial DNA repair. We searched for acquired vulnerabilities of cisplatin-resistant cancers to identify undiscovered therapy. We herein found that cisplatin resistance of cancer cells comes at a fitness cost of increased intracellular hypoxia. Then, we conceived an inspired strategy to combat the tumor drug resistance by exploiting the increased intracellular hypoxia that occurs as the cells develop drug resistance. Here, we constructed a hypoxia-amplifying DNA repair-inhibiting liposomal nanomedicine (denoted as HYDRI NM), which is formulated from a platinum(IV) prodrug as a building block and payloads of glucose oxidase (GOx) and hypoxia-activatable tirapazamine (TPZ). In studies on clinically relevant models, including patient-derived organoids and patient-derived xenograft tumors, the HYDRI NM is able to effectively suppress the growth of cisplatin-resistant tumors. Thus, this study provides clinical proof of concept for the therapy identified here.

Identification of key genes associated with sepsis patients infected by staphylococcus aureus through weighted gene co-expression network analysis.

The prevention and treatment of staphylococcus aureus septicemia is one of the thorniest problems in modern medicine. However, as the underlying pathogenesis of sepsis is still unclear, there is currently no golden standard for clinical diagnosis. In this study, we used GSE33341 dataset for differentially expressed gene (DEG) analysis and screened out 857 differentially expressed genes associated with staphylococcus aureus infection. The module having the highest correlation with clinical features of sepsis was screened by weighted gene co-expression network analysis (WGCNA). The genes in the selected module and the differentially expressed genes were represented in Venn diagram, and 59 pathogenic genes at the intersection were obtained. GO and KEGG analysis showed that these genes were mainly related to aerobic respiration, cellular stress response, mitochondrial electron transport, mitochondrial transport, oxidative phosphorylation. Kaplan-Meier was used to analyze the influence of the top 10 key genes on the prognosis of sepsis patients. The results showed that the high expression of NDUFA4, NDUFB3, COX7A2, ATP5J and COX7C was significantly correlated with the poor overall survival (OS) in patients with bacterial sepsis. These findings may potentially provide a reference for the diagnosis and treatment of bacterial septicemia.

In Vivo Real-Time Pharmaceutical Evaluations of Near-Infrared II Fluorescent Nanomedicine Bound Polyethylene Glycol Ligands for Tumor Photothermal Ablation.

Pharmaceutical evaluations of nanomedicines are of great significance for their further launch into industry and clinic. Near-infrared (NIR) fluorescence imaging plays essential roles in preclinical drug development by providing important insights into the biodistributions of drugs in vivo with deep tissue penetration and high spatiotemporal resolution. However, NIR-II fluorescence imaging has rarely been exploited for in vivo real-time pharmaceutical evaluations of nanomedicine. Herein, we developed a highly emissive NIR-II luminophore to establish a versatile nanoplatform to noninvasively monitor the in vivo metabolism of nanomedicines bound various polyethylene glycol (PEG) ligands in a real-time manner. An alternative D-A-D conjugated oligomer (DTTB) was synthesized to achieve NIR-II emission peaked at ∼1050 nm with high fluorescence QYs of 13.4% and a large absorption coefficient. By anchoring with the DTTB molecule, intrinsically fluorescent micelles were fabricated and bound with PEG ligands at various chain lengths. In vivo NIR-II fluorescence and photoacoustic imaging results revealed that an appropriate PEG chain length could effectively contribute to the longer blood circulation and better tumor targeting. In vivo therapeutic experiments also confirmed the optimized nanomedicines have efficient photothermal elimination of tumors and good biosafety. This work offered an alternative highly fluorescent NIR-II material and demonstrated a promising approach for real-time pharmaceutical evaluation of nanomedicine in vivo.

Single-Photomolecular Nanotheranostics for Synergetic Near-Infrared Fluorescence and Photoacoustic Imaging-Guided Highly Effective Photothermal Ablation.

Multi-modality imaging-guided cancer therapy is considered as a powerful theranostic platform enabling simultaneous precise diagnosis and treatment of cancer. However, recently reported multifunctional systems with multiple components and sophisticate structures remain major obstacles for further clinical translation. In this work, a single-photomolecular theranostic nanoplatform is fabricated via a facile nanoprecipitation strategy. By encapsulating a semiconductor oligomer (IT-S) into an amphiphilic lipid, water-dispersible IT-S nanoparticles (IT-S NPs) are prepared. The obtained IT-S NPs have a very simple construction and possess ultra-stable near-infrared (NIR) fluorescence (FL)/photoacoustic (PA) dual-modal imaging and high photothermal conversion efficiency of 72.3%. Accurate spatiotemporal distribution profiles of IT-S NPs are successfully visualized by NIR FL/PA dual-modal imaging. With the comprehensive in vivo imaging information provided by IT-S NPs, tumor photothermal ablation is readily realized under precise manipulation of laser irradiation, which greatly improves the therapeutic efficacy without any obvious side effects. Therefore, the IT-S NPs allow high tumor therapeutic efficacy under the precise guidance of FL/PA imaging techniques and thus hold great potential as an effective theranostic platform for future clinical applications.

Crx Is Posttranscriptionally Regulated by Light Stimulation in Postnatal Rat Retina.

Cone rod homeobox (Crx) plays a key role at the center of a regulatory network that coordinates many pathways in the retina. Its abnormal expression induces retinal disorders. However, the underlying regulatory mechanism of Crx expression is not well defined. Here, we present data that show that the levels of Crx mRNA were inconsistent with that of Crx protein in primary retinal neurocytes cultured in light conditions. Crx protein levels were significantly higher (2.56-fold) in cells cultured in the dark than in cells cultured in light, whereas Crx mRNA was not changed in either type of cell. Moreover, the expression of Crx protein showed a significant light intensity-dependent decrease. Consistently, Crx downstream genes rhodopsin and arrestin also decreased in retinal neurocytes upon light exposure. Furthermore, Crx promoter activity assay performed in primary retinal neurocytes further indicated that light exposure and darkness did not affect its inducibility. In addition, the inconsistency between Crx mRNA and protein expression after light exposure was not observed in 661w cells transfected with plasmid pcDNA3.1-Crx, suggesting that the inconsistency between Crx mRNA and protein induced by light was specific to the endogenous Crx. More importantly, this observation was confirmed in vivo in postnatal day 15 (P15) retinas but not in adult retinas, further implicating that the posttranscriptional regulation mechanism may be involved in Crx expression in the developing retina. Therefore, our study sheds light on the mechanism of Crx expression in postnatal rat retina.

Stimuli-responsive polymeric nanomaterials for rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a long-term inflammatory disease derived from an autoimmune disorder of the synovial membrane. Current therapeutic strategies for RA mainly aim to hamper the macrophages' proliferation and reduce the production of pro-inflammatory cytokines. Therefore, the accumulation of therapeutic agents targeted at the inflammatory site should be a crucial therapeutic strategy. Nowadays, the nanocarrier system incorporated with stimuli-responsive property is being intensively studied, showing the potentially tremendous value of specific therapy. Stimuli-responsive (i.e., pH, temperature, light, redox, and enzyme) polymeric nanomaterials, as an important component of nanoparticulate carriers, have been intensively developed for various diseases treatment. A survey of the literature suggests that the use of targeted nanocarriers to deliver therapeutic agents (nanotherapeutics) in the treatment of inflammatory arthritis remains largely unexplored. The lack of suitable stimuli-sensitive polymeric nanomaterials is one of the limitations. Herein, we provide an overview of drug delivery systems prepared from commonly used stimuli-sensitive polymeric nanomaterials and some inorganic agents that have potential in the treatment of RA. The current situation and challenges are also discussed to stimulate a novel thinking about the development of nanomedicine.

Artesunate induces mitochondria-mediated apoptosis of human retinoblastoma cells by upregulating Kruppel-like factor 6.

Retinoblastoma (RB) is the most common primary intraocular malignancy in children. Intravitreal chemotherapy achieves favorable clinical outcomes in controlling RB vitreous seeds, which are a common reason for treatment failure. Thus, a novel, effective and safe intravitreal chemotherapeutic drug is urgently required. The malaria drug artesunate (ART) recently demonstrated remarkable anticancer effects with mild side effects. The purpose of this study is to investigate the anti-RB efficacy, the underlying mechanism and the intraocular safety of ART. Herein, we verified that ART inhibits RB cell viability and induces cell apoptosis in a dose- and time-dependent manner. Microarray analysis revealed that Kruppel-like factor 6 (KLF6) was upregulated after ART treatment, and this was further confirmed by real-time PCR and western blot assays. Silencing of KLF6 expression significantly reversed ART-induced RB cell growth inhibition and apoptosis. Furthermore, ART activated mitochondria-mediated apoptosis of RB cells, while silencing KLF6 expression significantly inhibited this effect. In murine xenotransplantation models of RB, we further confirmed that ART inhibits RB tumor growth, induces tumor cell apoptosis and upregulates KLF6 expression. In addition, KLF6 silencing attenuates ART-mediated inhibition of tumor growth in vivo. Furthermore, we proved that intravitreal injection of ART in Sprague-Dawley (SD) rats is safe, with no obvious retinal function damage or structural disorders observed by electrophysiology (ERG), fundal photographs, fundus fluorescein angiography (FFA) or optical coherence tomography (OCT) examinations. Collectively, our study revealed that ART induces mitochondrial apoptosis of RB cells via upregulating KLF6, and our results may extend the application of ART to the clinic as an effective and safe intravitreal chemotherapeutic drug to treat RB, especially RB with vitreous seeds.

[Endodontic-periodontal combined therapy for type â ¢ dens invaginatus in maxillary lateral incisor: a case report].

We report a clinical case of type Ⅲ dens invaginatus with endodontic-periodontal lesion in a maxillary lateral incisor. The palatal radicular anomaly predisposed the tooth to periodontal lesions. The caries along the palatal groove caused tooth pulp necrosis and periapical lesions. By means of microscopic root canal therapy, apical surgery, and guided periodontal tissue regeneration, the apical and periodontal infection were controlled, and the affected tooth was retained.