bZIP transcription factors regulate diverse processes in eukaryotic cells. Arabidopsis bZIP members of the C and S1 groups form heterodimers and synergistically control metabolic reprogramming during stress responses. However, their functional characterization is complicated due to an overlapping heterodimerization network and high redundancy. In this study, we develop a simple but powerful approach for generating dominant negative mutants of bZIP factors with high specificity. By applying in vitro DNA-binding, reporter gene and protoplast two-hybrid assays, and plant mutant analysis, we show that phosphorylation-mimicking substitution of conserved serines in the DNA-binding domain of bZIP monomeric subunits suffices for the disruption of the interaction of both bZIP homo- and heterodimers with cognate DNA. This results in the transcriptional inactivation of target genes. The dominant-negative effect is achieved by the unaltered function of the intrinsic nuclear localization signal and dimerization properties of the mutated bZIP protein. Our findings not only reveal an additional regulatory mechanism of bZIP10 intracellular localization, but also provide evidence of the involvement of bZIP53 in the diurnal adjustments of amino acid metabolism. Our data demonstrate the advantages and the suitability of this new approach for the artificial inactivation of bZIP transcription factors in plants, and it may also be of use for other organisms.

We examined virological outcomes, patterns of acquired HIV drug resistance (ADR), correlates of virological failure (VF) and acquired drug resistance among fisherfolk on first-line ART.

Pyrenophoric acid (P-Acid), P-Acid B, and P-Acid C are three phytotoxic sesquiterpenoids produced by the ascomycete seed pathogen Pyrenophora semeniperda, a fungus proposed as a mycoherbicide for biocontrol of cheatgrass, an extremely invasive weed. When tested in cheatgrass bioassays, these metabolites were able to delay seed germination, with P-Acid B being the most active compound. Here, we have investigated the cross-kingdom activity of P-Acid B and its mode of action, and found that it activates the abscisic acid (ABA) signaling pathway in order to inhibit seedling establishment. P-Acid B inhibits seedling establishment in wild-type Arabidopsis thaliana, while several mutants affected in the early perception as well as in downstream ABA signaling components were insensitive to the fungal compound. However, in spite of structural similarities between ABA and P-Acid B, the latter is not able to activate the PYR/PYL family of ABA receptors. Instead, we have found that P-Acid B uses the ABA biosynthesis pathway at the level of alcohol dehydrogenase ABA2 to reduce seedling establishment. We propose that the fungus P. semeniperda manipulates plant ABA biosynthesis as a strategy to reduce seed germination, increasing its ability to cause seed mortality and thereby increase its fitness through higher reproductive success.

There is mounting evidence that our environment and lifestyle has an impact on epigenetic regulatory mechanisms, such as DNA methylation. It has been suggested that these molecular processes may mediate the effect of risk factors on disease susceptibility, although evidence in this regard has been challenging to uncover. Using genetic variants as surrogate variables, we have used two-sample Mendelian randomization (2SMR) to investigate the potential implications of putative changes to DNA methylation levels on disease susceptibility.

Group II introns are ribozymes that can excise themselves from precursor-RNA transcripts, but plant organellar group II introns have structural deviations that inhibit ribozyme activity. Therefore, splicing of these introns requires the assistance of nuclear- and/or organellar-encoded splicing factors; however, how these splicing factors function remains unclear. In this study, we report the functions and interactions of two splicing factors, PPR-SMR1 and Zm-mCSF1, in intron splicing in maize mitochondria. PPR-SMR1 is a SMR domain-containing pentatricopeptide repeat (PPR) protein and Zm-mCSF1 is a CRM domain-containing protein, and both are targeted to mitochondria. Loss-of-function mutations in each of them severely arrests embryogenesis and endosperm development in maize. Functional analyses indicate that PPR-SMR1 and Zm-mCSF1 are required for the splicing of most mitochondrial group II introns. Among them, nad2-intron 2 and 3, and nad5-intron 1 are PPR-SMR1/Zm-mCSF1-dependent introns. Protein interaction assays suggest that PPR-SMR1 can interact with Zm-mCSF1 through its N-terminus, and that Zm-mCSF1 is self-interacting. Our findings suggest that PPR-SMR1, a novel splicing factor, acts in the splicing of multiple group II introns in maize mitochondria, and the protein-protein interaction between it and Zm-mCSF1 might allow the formation of large macromolecular splicing complexes.

Leaves within crop canopies experience variable light over the course of a day, which greatly affects photosynthesis and crop productivity. Little is known about the mechanisms of the photosynthetic response to fluctuating light and their genetic control. Here, we examined gas exchange, metabolite levels, and chlorophyll fluorescence during the photosynthetic induction response in an Oryza sativa indica cultivar with high yield (Takanari) and a japonica cultivar with lower yield (Koshihikari). Takanari had a faster induction response to sudden increases in light intensity than Koshihikari, as demonstrated by faster increases in net CO2 assimilation rate, stomatal conductance, and electron transport rate. In a simulated light regime that mimicked a typical summer day, the faster induction response in Takanari increased daily CO2 assimilation by 10%. The faster response of Takanari was explained in part by its maintenance of a larger pool of Calvin-Benson cycle metabolites. Together, the rapid responses of electron transport rate, metabolic flux, and stomatal conductance in Takanari contributed to the greater daily carbon gain under fluctuating light typical of natural environments.

The key to successful treatment of cerebral venous‑sinus occlusion (CVO) is the rapid recanalization of the sinus following venous‑sinus occlusion; however, rapid recanalization of the sinus may also cause secondary cerebral injury. The present study examined mechanical thrombectomy‑related brain injury and the possible molecular mechanisms following CVO recanalization, and investigated the protective effect of glycyrrhizin (GL) in CVO recanalization. The cerebral venous sinus thrombosis (CVST) model was induced in rats using 40% FeCl3. Mechanical thrombectomy was performed at 6 h post‑thrombosis. GL was administered to rats following thromboembolism. Neurological function and brain water content were measured prior to sacrifice of the rats. Serum malondialdehyde, superoxide dismutase and nitric‑oxide synthase concentrations were measured. The expression levels of high‑mobility group box 1 (HMGB1) and receptor of advanced glycation end products (RAGE) and its downstream inflammatory mediators were measured in serum and brain tissues. Rapid CVO recanalization caused brain injury, and the brain parenchymal damage and neurological deficits caused by CVO were not completely restored following recanalization. Similarly, following rapid recanalization in the venous sinus, the expression levels of HMGB1 and RAGE were lower than those in the CVST group, but remained significantly higher than those of the sham group. The combination of mechanical thrombectomy and GL improved cerebral infarction and cerebral edema in rats, and inhibited the extracellular transport of HMGB1, and the expression of downstream inflammatory factors and oxidative‑stress products. The administration of exogenous recombinant HMGB1 reversed the neural protective effects of GL. In conclusion, mechanical thrombectomy subsequent to CVO in rats can cause brain injury following recanalization. HMGB1 and RAGE promote inflammation in the process of brain injury following recanalization. GL has a relatively reliable neuroprotective effect on brain injury by inhibiting HMGB1 and its downstream inflammatory factors, and decreasing oxidative stress.

The present study aimed to screen crucial micro (mi)RNAs and long non‑coding (lnc)RNAs involved in the development of ossification of ligamentum flavum (OLF) based on the miRNA‑mRNA and lncRNA‑miRNA‑mRNA competing endogenous (ce)RNA regulatory network analyses, which are rarely reported. The differentially expressed genes (DEGs), differentially expressed lncRNAs (DELs) and differentially expressed miRNAs (DEMs) between 4 OLF and 4 healthy controls were identified using two microarray datasets GSE106253 and GSE106256 collected from the Gene Expression Omnibus database. A protein‑protein interaction (PPI) network was constructed, followed by calculation of topological characteristics and sub‑module analysis in order to obtain hub DEGs. The miRNA‑mRNA and lncRNA‑miRNA networks that were established based on their interaction pairs, obtained from miRwalk and starBase databases, respectively, were integrated to form the ceRNA network. The underlying functions of mRNAs were predicted using the Database for Annotation, Visualization and Integrated Discovery (DAVID). The present study screened 828 DEGs, 119 DELs and 81 DEMs between OLF and controls. PPI network and module analyses identified interleukin (IL)10, adenylate cyclase (ADCY)5, suppressor of cytokine signaling (SOCS)3, G protein subunit gamma (GNG) 4, collagen type II α 1 chain (COL2A1) and collagen type XIII α 1 chain (COL13A1) as hub genes. The miRNA‑mRNA network analysis demonstrated IL10 could be regulated by miR‑210‑3p, while COL13A1 and COL2A1 could be modulated by miR‑329‑3p and miR‑222‑5p, respectively. lncRNA‑miRNA‑mRNA ceRNA network analysis identified that small nucleolar RNA host gene 16‑hsa‑miR‑196a‑5p‑SOCS3, ankyrin repeat and SOCS box containing 16‑AS1‑hsa‑miR‑379‑5p‑GNG4, nuclear enriched abundant transcript 1‑has‑miR‑181b‑5p‑ADCY5, rhophilin 1‑AS1‑hsa‑miR‑299‑3p‑WNT7B interaction axes may be crucial. DAVID analysis predicted IL10, ADCY5, GNG4 and SOCS3 were involved in 'adaptive immune response', 'Chemokine signaling pathway' and 'regulation of apoptosis' processes, while COL2A1, COL13A1 and WNT7B may be ossification related. In conclusion, the identification of these crucial miRNAs and lncRNAs may be conducive for explaining the pathogenesis of OLF and provide certain natural, endogenous and nontoxic drug targets for the treatment of OLF.

Nucleoside diphosphate kinase 4 (NME4) is abnormally expressed in a variety of cancer types. However, the function of the NME4 gene in non‑small cell lung cancer (NSCLC) remains to be elucidated. In order to investigate the role of NME4 in NSCLC, the present study detected the expression of the NME4 gene in the Cancer Genome Atlas database, and in BEAS‑2B, NCI‑H1299 and A549 cell lines. NME4 was significantly overexpressed in NSCLC tissues and NSCLC cell lines. Furthermore, lentivirus‑mediated knockdown vector infection, cell proliferation, cell cycle, apoptosis, colony formation and MTT assays were conducted to explore the effect of NME4 on NSCLC in vitro. After knockdown of NME4 with short hairpin RNA, the cell cycle was arrest at the G1 phase, and proliferation and colony formation were inhibited in the NCI‑H1299 and A549 cell lines. The present results suggested that NME4 may serve as a novel tumor promoter, capable of enhancing NSCLC progression by overcoming cell cycle arrest and promoting proliferation.

Arginine/serine‑rich coiled coil 1 (RSRC1) is a gene which plays a significant role in the constitutive and alternative splicing of mRNA and transcriptional regulation. It has been implicated in various neurological disorders, as well as in cancer. However, its role in gastric cancer (GC) remains unknown. Thus, the present study aimed to investigate the role of RSRC1 in GC. RSRC1 expression in GC tissues was determined by RT‑qPCR and immunohistochemical staining. The effects of RSRC1 on cell proliferation and migration were detected using a Cell Counting Kit‑8 assay, 5‑ethynyl‑2'‑deoxyuridine (EdU) incorporation assay and a Transwell migration assay. Western blot analysis and RT‑qPCR were used to explore the molecular mechanisms of of action of RSRC1 in GC. The results indicated that RSRC1 expression was downregulated in GC tissues compared to paired normal tissues and the reduced expression of RSRC1 was shown to contribute to a poor prognosis of patients with GC. RSRC1 knockdown promoted the proliferation and migration of GC cells. In addition, the knockdown of RSRC1 decreased the expression of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), a potent tumor suppressor gene controlling cellular growth and viability. On the whole, the findings of the present study indicate that RSRC1 functions as a tumor suppressor gene in GC and that it may exert its effects by regulating PTEN expression.

The present study investigated the effect of dexmedetomidine on hippocampal inflammation and cognitive function in rats with postoperative cognitive dysfunction (POCD). A total of 80 healthy male Sprague Dawley rats were used, 72 of which developed POCD. The rats were randomly divided into four groups: The control, model, low‑dose and high‑dose dexmedetomidine anesthesia groups. A POCD model was established and dexmedetomidine was administered. Cognitive function tests were performed and expression levels of interleukin 1β (IL‑1β), tumor necrosis factor‑α (TNF‑α) and NF‑κB biomarkers were evaluated on the first, third and seventh day following modeling. The cognitive function of rats was measured using a Y‑maze test. The expression levels of IL‑1β and TNF‑α in the hippocampus were determined by ELISA. The protein expression levels of NF‑κB p65 in the hippocampus were determined by western blotting. It was revealed that at 1, 3 and 7 days after surgery, there were no alterations in the exercise ability of rats in the different groups, as reflected by the number of rats passing the alternative arms in the Y‑maze. On the first and third day after surgery, the cognitive dysfunction reflected by the alteration scores of the low‑dose and high‑dose dexmedetomidine anesthesia groups were significantly higher than those of the model group, and the increase in the high‑dose group was more pronounced. Additionally, on the first day after surgery, the expression levels of IL‑1β, TNF‑α and NF‑κB in the hippocampi of rats in the low‑ and high‑dose dexmedetomidine anesthesia groups were significantly lower than those in the model group, and the decrease was more pronounced in the high‑dose group. At 7 days after surgery, the differences in expression levels of IL‑1β, TNF‑α and NF‑κB in the hippocampus among groups were not identified to be statistically significantly different. Taken together, the results of the present study indicated that dexmedetomidine may inhibit hippocampal inflammation induced by surgical trauma, and that dexmedetomidine may effectively improve postoperative cognitive function in rats.

Glucagon‑like peptide‑1 (GLP‑1) and its receptor (GLP‑1R) exert cardioprotective effects after myocardial ischemia and reperfusion (MI/R) in animal models and human clinical trials. Receptor imaging with positron emission tomography (PET) provides a non‑invasive method for monitoring GLP‑1R expression. In the present study, a fluorine‑18‑labeled aluminum fluoride exendin‑4 analog [18F‑AlF conjugated with 1,4,7‑triazacyclononanetriacetic acid (NOTA)‑maleimide (MAL)‑Cys40‑exendin‑4] was synthesized and evaluated in a rat MI/R model for GLP‑1R imaging. NOTA‑MAL‑Cys40‑exendin‑4 was synthesized by coupling Cys40‑exendin‑4 with NOTA‑MAL. NOTA‑MAL‑Cys40‑exendin‑4 was then conjugated with 18F‑AlF to obtain 18F‑AlF‑NOTA‑MAL‑Cys40‑exendin‑4. The yield of 18F‑AlF‑NOTA‑MAL‑Cys40‑exendin‑4 was 18.5±3.4% (not decay corrected). The process was completed within ~30 min. In rat MI/R models, the tracer exhibited specific binding to GLP‑1R and an appropriate signal‑to‑noise ratio. At 8 h post‑MI/R, tracer uptake reached its peak [0.35±0.053% of injected dose (%ID)/g; n=6] in ischemic myocardium. Localized tracer uptake decreased 1 day (0.20±0.032 %ID/g; n=6) and 3 days (0.16±0.017 %ID/g; n=6) post‑MI/R compared with 8 h post‑MI/R, but still remained higher compared with sham‑operated groups (0.06±0.012 %ID/g; n=6). Pre‑injected unlabeled exendin‑4 effectively blocked tracer accumulation (0.09±0.041 %ID/g; n=6). In conclusion, 18F‑AlF‑NOTA‑MAL‑Cys40‑exendin‑4 demonstrated favorable characteristics for GLP‑1R imaging following MI/R. PET imaging using 18F‑AlF‑NOTA‑MAL‑Cys40‑exendin‑4 in rodent hearts after MI/R revealed a dynamic pattern of GLP‑1R upregulation.

Although miRNAs have been implicated in the osteogenic differentiation of stem cells, their role in bone repair and reconstruction in tissue‑engineered bone grafts remains unclear. We previously reported that microRNA (miR)‑26a‑5p inhibited the osteogenic differentiation of adipose‑derived mesenchymal stem cells (ADSCs), and that antimiR‑26a‑5p exerted the opposite effect. In the present study, the role of miR‑26a‑5p‑ and antimiR‑26a‑5p‑modified ADSCs combined with biphasic calcium phosphate (BCP) scaffolds was evaluated in a rat femur defect model. The aim of the present study was to improve the understanding of the role of miR‑26a‑5p in bone regeneration in vivo, as well as to provide a new method to optimize the osteogenic ability of BCPs. ADSCs were infected with Lv‑miR‑26a‑5p, Lv‑miR‑NC, Lv‑antimiR‑26a‑5p or Lv‑antimiR‑NC respectively, and then combined with BCP scaffolds to repair rat femoral defects. Using X‑rays, micro‑computed tomography and histology at 2, 4, and 8 weeks postoperatively, the quantity and rate of bone regeneration were analyzed, revealing that they were the highest in animals treated with antimiR‑26a‑5p and the lowest in the miR‑26a‑5p treatment group. The expression levels of osteocalcin, collagen I, Runt‑related transcription factor 2, Wnt family member 5A and calmodulin‑dependent protein kinase II proteins were positively correlated with the bone formation rate. Taken together, the present results demonstrated that miR‑26a‑5p inhibited bone formation while antimiR‑26a‑5p accelerated bone formation via the Wnt/Ca2+ signaling pathway. Therefore, antimiR‑26a‑5p‑modified ADSCs combined with BCP scaffolds may be used to construct an effective tissue‑engineering bone graft for bone repair and reconstruction.

Atopic dermatitis (AD), a chronic inflammatory skin disease, is characterized by intense itching and recurrent eczematous lesions. Sulforaphane is known to attenuate oxidative stress, and tissue or cell damage in cerebral ischemia, brain inflammation and intracerebral hemorrhage. In the present study, a 2,4‑dinitrochlorobenzene (DNCB)‑induced AD mouse model was developed, and ear thickness, dermatitis score, eosinophil count, mast cell infiltration, and serum IgE levels were measured in DNCB‑induced AD and sulforaphane‑treated groups to demonstrate the therapeutic effects of sulforaphane. AD symptoms of DNCB‑induced mice were attenuated by sulforaphane treatment compared with those of negative control mice; furthermore, eosinophil count, mast cell infiltration and serum IgE levels were also reduced by sulforaphane treatment in DNCB‑induced AD mice. Western blot assays revealed that the expression levels of nuclear factor‑E2‑related factor 2 (Nrf2) and heme oxygenase-1 (HO‑1), which exhibit oxidation resistance, were increased by sulforaphane treatment in DNCB‑induced AD mice. The present study suggested that sulforaphane exerted a therapeutic effect in the AD mouse model through the activation of the Nrf2/HO‑1 axis as well as the suppression of Janus kinase 1/STAT3 signaling pathway.

The intestinal epithelium is a monolayer of cells arranged side‑by‑side and connected by tight junction (TJ) proteins expressed at the apical extreme of the paracellular membrane. This layer prevents stress‑induced inflammatory responses, thus helping to maintain gut barrier function and gut homeostasis. The aim of the present study was to evaluate the effects of chronic immobilization stress on the colonic expression of various parameters of homeostasis. A total of two groups of female BALB/c mice (n=6) were included: A stressed group (short‑term immobilization for 2 h/day for 4 consecutive days) and an unstressed (control) group. Colon samples were obtained to detect neutrophils and goblet cells by optical microscopy, TJ protein expression (occludin, and claudin ‑2, ‑4, ‑7, ‑12 and ‑15) by western blotting, mRNA levels of TJ genes and proinflammatory cytokines [tumor necrosis factor (TNF)‑α, interleukin (IL)‑1β, ‑6 and ‑8] by reverse transcription‑quantitative PCR, fecal lactoferrin by ELISA and the number of colony‑forming units of aerobic bacteria. Compared with goblet cells in control mice, goblet cells were enlarged and reduced in number in stressed mice, whereas neutrophil cellularity was unaltered. Stressed mice exhibited reduced mRNA expression for all evaluated TJ mRNAs, with the exception of claudin‑7, which was upregulated. Protein levels of occludin and all claudins (with the exception of claudin‑12) were decreased in stressed mice. Fecal lactoferrin, proinflammatory cytokine mRNA levels and aerobic bacterial counts were all increased in the stressed group. These results indicated that immobilization stress induced proinflammatory and potential remodeling effects in the colon by decreasing TJ protein expression. The present study may be a useful reference for therapies aiming to regulate the effects of stress on intestinal inflammatory dysfunction.

Pre-mRNA splicing is a complex process requiring the identification of donor site, acceptor site, and branch point site with an adjacent polypyrimidine tract sequence. Splicing is regulated by splicing regulatory elements (SREs) with both enhancer and suppressor functions. Variants located in exonic regions can impact splicing through dysregulation of native splice sites, SREs, and cryptic splice site activation. While splicing dysregulation is considered primary disease-inducing mechanism of synonymous variants, its contribution toward disease phenotype of non-synonymous variants is underappreciated.

We observed the death of insect caterpillars of Spodoptera exigua in the laboratory culture line and identified Serratia marcescens as the bacterial causative agent of the insect death. We confirmed that S. marcescens had insecticidal activity against S. exigua and caused high mortality of larvae. The LC50 values of S. marcescens CFU per 1 cm2 of insect diet surface were similar for all isolates. Our research reports novel strains with high pesticidal activity as candidates for future research on a new bioinsecticide. As bioinsecticides cannot be harmful to non-target organisms, we determined the pathogenic properties of S. marcescens to humans. We proved the ability of S. marcescens to damage mammalian epithelial cells. All strains had cytopathic effects to Vero cells with a cytotoxic index ranging from 51.2% ± 3.8% to 79.2% ± 4.1%. We found that all of the strains excreted catecholate siderophore - enterobactin. All isolates were resistant to sulfamethoxazole, tobramycin, gentamicin, cefepime, and aztreonam. We did not observe the ESBL phenotype and the integrons' integrase genes. Resistance to sulfamethoxazole was due to the presence of the sul1 or sul2 gene. The use of resistant S. marcescens strains that are pathogenic to humans in plant protection may cause infections difficult to cure and lead to the spread of resistance genes. The results of our study emphasize the necessity of determination of the safety to vertebrates of the bacteria that are proposed to serve as biocontrol agents. The novelty of our study lies in the demonstration of the indispensability of the bacteria verification towards the lack of hazardous properties to humans. We observed the death of insect caterpillars of Spodoptera exigua in the laboratory culture line and identified Serratia marcescens as the bacterial causative agent of the insect death. We confirmed that S. marcescens had insecticidal activity against S. exigua and caused high mortality of larvae. The LC50 values of S. marcescens CFU per 1 cm2 of insect diet surface were similar for all isolates. Our research reports novel strains with high pesticidal activity as candidates for future research on a new bioinsecticide. As bioinsecticides cannot be harmful to non-target organisms, we determined the pathogenic properties of S. marcescens to humans. We proved the ability of S. marcescens to damage mammalian epithelial cells. All strains had cytopathic effects to Vero cells with a cytotoxic index ranging from 51.2% ± 3.8% to 79.2% ± 4.1%. We found that all of the strains excreted catecholate siderophore – enterobactin. All isolates were resistant to sulfamethoxazole, tobramycin, gentamicin, cefepime, and aztreonam. We did not observe the ESBL phenotype and the integrons’ integrase genes. Resistance to sulfamethoxazole was due to the presence of the sul1 or sul2 gene. The use of resistant S. marcescens strains that are pathogenic to humans in plant protection may cause infections difficult to cure and lead to the spread of resistance genes. The results of our study emphasize the necessity of determination of the safety to vertebrates of the bacteria that are proposed to serve as biocontrol agents. The novelty of our study lies in the demonstration of the indispensability of the bacteria verification towards the lack of hazardous properties to humans.

Several nerve blocks can reduce the incidence of postherpetic neuralgia (PHN) as well as relieve acute zoster-related pain, but the long-term outcome of PHN has not been clearly determined. This study investigated the efficacy of selective nerve root block (SNRB) for herpes zoster (HZ) on the long-term outcome of PHN.

The biodegradability and clearance of metal-based nanomaterials have been questioned worldwide, which have greatly limited their clinical translation. Herein, ultrathin manganese dioxide (MnO2) nanosheets with broad near-infrared (NIR) absorption and pH-dependent degradation properties were prepared. After being modified with polyethylene glycol-cyclic arginine-glycineaspartic acid tripeptide (PEG-cRGD), the MnO2 nanosheets were then used as photothermal agent and nanocarrier to encapsulate chlorin e6 (Ce6) for targeted photothermal (PTT) and photodynamic (PDT) of cancer. As expected, the MnO2-PEG-cRGD nanosheets show high Ce6 loading capacity (351 mg/g), superb photothermal conversion performance (37.2%) and excellent colloidal stability. These nanosheets also exhibit pH-dependent and NIR-induced Ce6 release. Furthermore, the MnO2 nanosheets can be degraded by reacting with hydrogen peroxide in the acidic microenvironment, which are able to elevate the oxygen concentration in situ and thus reverses the tumor hypoxia. Thanks to these favorable properties and the cRGD-mediated tumor-targeted ability, the fabricated MnO2-PEG-cRGD/Ce6 nanocomposites can be effectively up taken by alpha-v beta-3 (αvβ3) integrin over-expressed prostatic carcinoma PC3 cells and achieve favorable therapeutic outcomes under a single 660 nm NIR laser, which is also verified by in vitro studies. The biodegradable MnO2-PEG-cRGD/Ce6 nanosheets developed in this work can be a promising nanoplatform for synergetic PTT/PDT cancer therapy.

Purpose: With the increase of population aging and the proportion of overweight and obese, a growing number of people are suffering from diabetes. Insulin (INS) as the most widely used hypoglycemic agent was always chosen as the most effective treatment method of diabetes. In this study, fumaryl diketopiperazine (FDKP) was used as a carrier for the pulmonary delivery of insulin. Patients and methods: The INS-loaded FDKP microspheres (INS@FDKP-MPs) were prepared by spray drying and physicochemical properties (drug loading, particle size, flowability, moisture content, morphology, and crystalline state) were further investigated. Pharmacodynamics was investigated on diabetic model rats administrated by intratracheal insufflation. Results: The INS-loaded FDKP microspheres show satisfied flowability and in vitro deposition with FPF 50.2% and MMAD 3.45 ± 0.13 μm, and the blood glucose level was significantly decreased. Moreover, no inflammatory reaction was observed during the safety study. Conclusion: To sum up, the aim was to develop a non-injection system for insulin, INS@FDKP-MPs powder inhalation with high dose, low toxicity, and good lung deposition inhalation could rapidly decrease the blood glucose level without immune stimulation, which shows remarkably potential on diabetes treatment by pulmonary delivery route.