CircPGM5 regulates Foxo3a phosphorylation via MiR-21-5p/MAPK10 axis to inhibit bladder cancer progression.

Bladder cancer (BC) is one of the most prevalent malignant tumors worldwide, and the incidence is especially higher in males. Extensive evidence has demonstrated the pivotal role of circular RNAs (circRNAs) in BC progression. However, the exact regulatory mechanism of circRNAs in BC remains incompletely elucidated and warrants further exploration. This study screened a novel circRNA-circPGM5 from thousands of circRNAs by high-throughput sequencing. We found that circPGM5, originating from the PGM5 gene, was significantly lower expressed in BC tissues. Quantitative real-time PCR (qRT-PCR) verified that circPGM5 showed relatively low expression in 50 pairs of BC tissues and EJ and T24 cells. Notably, circPGM5 expression was correlated with stage, grade, and lymphatic metastasis of BC. Through RNA-FISH assay, we confirmed that circPGM5 predominantly localized in the cytoplasm. Functionally, overexpression of circPGM5 inhibited the proliferation, migration, and invasion of BC cells in vitro. Remarkably, circPGM5 demonstrated markedly significant tumor growth and metastasis suppression in vivo. Mechanistically, we discovered that circPGM5 upregulated the mitogen-activated protein kinase 10 (MAPK10) expression by influencing the oncogenic miR-21-5p activity through miR-21-5p absorption. This modulation of MAPK10 impacted the phosphorylation of the tumor suppressor Foxo3a in BC. In conclusion, our findings uncovered the tumor-suppressing role of circPGM5 in BC via the miR-21-5p/MAPK10/Foxo3a axis.

Etiological surveillance of viral diarrhea from 2017 to 2019 in Zhangzhou city, Fujian province, China.

Background: Viral diarrhea is one of the major causes of morbidity and mortality in children. This study aimed to conduct etiological surveillance of viral diarrhea in Zhangzhou city, Fujian province, China, from 2017 to 2019 to identify the prevalence, distribution, and characteristics of viral pathogens causing gastrointestinal infections in the region. Methods: Stool samples were collected from patients with acute diarrhea in Zhangzhou city, Fujian province, China, from 2017 to 2019. Rotavirus, norovirus, astrovirus, and adenovirus were detected using fluorescence immunochromatography assay. Results: Of the total 5,627 samples that were collected, at least one of the viruses (rotavirus, norovirus, astrovirus and adenovirus) was found to be positive in 1,422 samples. Rotavirus, norovirus, astrovirus, and adenovirus, were detected in 53.73, 16.68, 15.52, and 14.97%, respectively. Mixed infections were determined in 17.65% of the positive samples. The predominant mixed infections observed were a combination of norovirus and astrovirus, followed by rotavirus and norovirus, and rotavirus and astrovirus. The highest positive rate was observed in the 12-23-month group for rotavirus and adenovirus, while a significantly higher positive rate was observed for norovirus and astrovirus in the 6-11-month group. Conclusion: These findings from this etiological surveillance highlight the significant burden of viral diarrhea in Zhangzhou city, with rotavirus being the predominant pathogen. The identification of common mixed infections provides insights into the complex nature of viral diarrhea transmission. Target interventions and public health strategies should be implemented, particularly during the winter and spring seasons, to prevent and control the spread of viral pathogens causing gastrointestinal infections in this region.

(±)-Hypernumqulins A-H: Eight pairs of unexpected [2+2] cycloaddition sesquiterpenoid alkaloid with 6/6/6/4/10 ring system from Hypericum monogynum L.

(±)-Hypernumqulins A-H (1-8), eight pairs of enantiomeric quinoline alkaloids fused with an isopentenyl and a germacrane-type sesquiterpenoid, featuring an unprecedented skeleton with 6/6/6/4/10 ring system, were isolated from Hypericum monogynum L. under the guidance of molecular networking strategy. Their structures including absolute configuration were elucidated by NMR spectroscopy analysis, X-ray crystallography and quantum chemical calculation. The proposed [2+2] cycloaddition may play a key biogenic step in building the unexpected skeleton. Most of the isolates exhibited cytotoxicity with IC50 values ranging from 2.82 ± 0.03 to 45.25 ± 1.26 µM against MCF-7, A549 or SGC7901 cells. Furthermore, compounds (±)-1 and (-)-1 could induce apoptosis by upregulating the protein expression level of Bax and downregulating of Bcl-2 in MCF-7 cells. These findings provided the first example of germacrane sesquiterpene quinoline alkaloids, and supported the possibilities for the development of new anti-tumor agents.

Selective Activation of Lattice Oxygen Site Through Coordination Engineering to Boost the Activity and Stability of Oxygen Evolution Reaction.

Although Ru-based materials are among the outstanding catalysts for the oxygen evolution reaction (OER), the instability issue still haunts them and impedes the widespread application. The instability of Ru-based OER catalysts is generally ascribed to the formation of soluble species through the over-oxidation of Ru and structural decomposition caused by involvement of lattice oxygen. Herein, an effective strategy of selectively activating the lattice oxygen around Ru site is proposed to improve the OER activity and stability. Our synthesized spinel-type electrocatalyst of Ru and Zn co-doped Co3O4 showed an ultralow overpotential of 172 mV at 10 mA cm-2 and a long-term stability reaching to 100 hours at 10 mA cm-2 for alkaline OER. The experimental results and theoretical simulations demonstrated that the lattice oxygen site jointly connected with the octahedral Ru and tetrahedral Zn atoms became more active than other oxygen sites near Ru atom, which further lowered the reaction energy barriers and avoided generating excessive oxygen vacancies to enhance the structural stability of Ru sites. The findings hope to provide a new perspective to improve the catalytic activity of Ru-incorporated OER catalysts and the stability of lattice-oxygen-mediated mechanism.

Ultralow-Noise MoS2/Type II Superlattice Mixed-Dimensional van der Waals Barrier Long-Wave Infrared Detector.

Low-noise, high-performance long-wave infrared detectors play a crucial role in diverse applications, including in the industrial, security, and medical fields. However, the current performance of long-wave detectors is constrained by the noise associated with narrow bandgaps. Therefore, exploring novel heterostructures for long-wavelength infrared detection is advantageous for the development of compact and high-performance infrared sensing. In this investigation, we present a MoS2/type II superlattice mixed-dimensional van der Waals barrier long-wave infrared detector (Mixed-vdWH). Through the design of the valence band barrier, substantial suppression of device dark noise is achieved, resulting in 2 orders of magnitude reduction in dark current. The device exhibits outstanding performance, with D* reaching 4 × 1010 Jones. This integration approach synergizes the distinctive properties of two-dimensional layered materials (2DLM) with the well-established processing techniques of traditional three-dimensional semiconductor materials, offering a compelling avenue for the large-scale integration of 2DLM.

MiR-320 inhibits PRRSV replication by targeting PRRSV ORF6 and porcine CEBPB.

Porcine reproductive and respiratory syndrome (PRRS), a highly contagious disease caused by Porcine reproductive and respiratory syndrome virus (PRRSV), results in huge economic losses to the world pig industry. MiRNAs have been reported to be involved in regulation of viral infection. In our study, miR-320 was one of 21 common differentially expressed miRNAs of Meishan, Pietrain, and Landrace pig breeds at 9-h post-infection (hpi). Bioinformatics and experiments found that PRRSV replication was inhibited by miR-320 through directly targeting PRRSV ORF6. In addition, the expression of CCAAT enhancer binding protein beta (CEBPB) was also inhibited by miR-320 by targeting the 3' UTR of CEBPB, which significantly promotes PRRSV replication. Intramuscular injection of pEGFP-N1-miR-320 verified that miR-320 significantly inhibited the replication of PRRSV and alleviated the symptoms caused by PRRSV in piglets. Taken together, miR-320 have significant roles in the infection and may be promising therapeutic target for PRRS.

Measurement of the vertical distributions of atmospheric pollutants using an uncrewed aerial vehicle platform in Xi'an, China.

Vertical observations of atmospheric pollutants play crucial roles in a comprehensive understanding of the distribution characteristics and transport of atmospheric pollutants. A hexacopter uncrewed aerial vehicle equipped with miniature monitors was employed to measure the vertical distribution of atmospheric pollutants within a height of 1000 m at a rural site in Xi'an, China, in 2021. The concentrations of carbon monoxide (CO) and particulate matter (PM) showed generally decreasing trends with increasing height. The ozone (O3) concentration showed a general increasing trend with height followed by a gradual decreasing trend. Vertical decrements of PM2.5 and CO from 0 to 1000 m were significantly (p < 0.05) lower on observation days during summer (14.0 ± 8.1 µg m-3 and 8.7 ± 6.6 ppb, respectively), compared with those in winter (78.3 ± 14.1 µg m-3 and 34.8 ± 17.3 ppb, respectively). The horizontal transport of PM and CO mostly occurred in the morning and at night during winter observations at an altitude of 400-500 m. During the winter haze, the PM and CO profile concentrations below 500 m increased substantially with the decrease in the height of the thermal inversion layer. Vertical O3 transportation was observed in the afternoon and evening during summer, and a ∼37.7% (11.6 ppb) increase in ground-level O3 was observed in relation to vertical transport from the upper atmosphere. The results provide insights into the vertical distribution and transport of atmospheric pollutants in rural areas near cities.

Sarmentol H derived from Sedum sarmentosum Bunge directly targets FXR to mitigate cholestasis by recruiting SRC-1.

BACKGROUND: Farnesoid X receptor (FXR) is a vital receptor for bile acids and plays an important role in the treatment of cholestatic liver disease. In addition to traditional bile acid-based steroidal agonists, synthetic alkaloids are the most commonly reported non-steroidal FXR agonists. Sarmentol H is a nor-sesquiterpenoid obtained from Sedum sarmentosum Bunge, and in vitro screening experiments have shown that it might be related to the regulation of the FXR pathway in a previous study. PURPOSE: To investigate the therapeutic effects of sarmentol H on cholestasis and to determine whether sarmentol H directly targets FXR to mitigate cholestasis. Furthermore, this study aimed to explore the key amino acid residues involved in the binding of sarmentol H to FXR through site-directed mutagenesis. METHODS: An intrahepatic cholestasis mouse model was established to investigate the therapeutic effects of sarmentol H on cholestasis. In vitro experiments, including Co-Ip and FXR-EcRE-Luc assays, were performed to assess whether sarmentol H activates FXR by recruiting the receptor coactivator SRC1. CETSA, SIP, DARTS, and ITC were used to determine the binding of sarmentol H to FXR protein. The key amino acid residues for sarmentol H binding to FXR were analyzed by molecular docking and site-directed mutagenesis. Finally, we conducted in vivo experiments on wild-type and Fxr-/- mice to further validate the anticholestatic target of sarmentol H. RESULTS: Sarmentol H had significant ameliorative effects on the pathological conditions of cholestatic mice induced with ANIT. In vitro experiments suggested that it is capable of activating FXR and regulating downstream signaling pathways by recruiting SRC1. The target validation experiments showed that sarmentol H had the ability to bind to FXR as a ligand (KD = 2.55 µmol/L) and enhance the stability of its spatial structure. Moreover, site-directed mutagenesis revealed that THR292 and TYR365 were key binding sites for sarmentol H and FXR. Furthermore, knockout of the Fxr gene resulted in a significantly higher degree of ANIT-induced cholestatic liver injury than that in wild-type cholestatic mice, and the amelioration of cholestasis or regulatory effects on FXR downstream genes by sarmentol H also disappeared in Fxr-/- cholestatic mice. CONCLUSION: Sarmentol H is an FXR agonist. This is the first study to show that it exerts a significant therapeutic effect on cholestatic mice, and can directly bind to FXR and activate it by recruiting the coactivator SRC1.

Sandwich-type electrochemical immunosensing of CA125 by using nanoribbon-like Ti3C2Tx MXenes and toluidine blue/UIO-66-NH2.

CA125 (carbohydrate antigen 125) is an important biomarker of ovarian cancer, so developing effective method for its detection is of great significance. In the present work, a novel sandwich-like electrochemical immunosensor (STEM) of CA125 was constructed by preparing nanoribbon-like Ti3C2Tx MXenes (Ti3C2TxNR) to immobilize primary antibody (PAb) of CA125 and UIO-66-NH2 MOFs structure to immobilize second antibody (SAb) and electroactive toluidine blue (Tb) probe. In this designed STEM assay, the as-prepared Ti3C2TxNR nanohybrid offers the advantages in large surface area and conductivity as carrier, and UIO-66-NH2 provided an ideal platform to accommodate SAb and a large number of Tb molecules as signal amplifier. In the presence of CA125, the peak currents of Tb from the formed STEM structure increase with the increase of CA125 level. After optimizing the related control conditions, a wide linear range (0.2-150.0 U mL-1) and a very low detection limit (0.05 U mL-1) of CA125 were achieved. It's thus expected the developed STEM strategy has important applications for the detection of CA125.

Intravenous immunoglobulin alleviates Japanese encephalitis virus-induced peripheral neuropathy by inhibiting the ASM/ceramide pathway.

Japanese encephalitis virus (JEV) infection is considered a global public health emergency. Severe peripheral neuropathy caused by JEV infection has increased disability and mortality rates in recent years. Because there are very few therapeutic options for JEV infection, prompt investigations of the ability of clinically safe, efficacious and globally available drugs to inhibit JEV infection and ameliorate peripheral neuropathy are urgently needed. In this study, we found that high doses of intravenous immunoglobulin, a function inhibitor of acid sphingomyelinase (FIASMA), inhibited acid sphingomyelinase (ASM) and ceramide activity in the serum and sciatic nerve of JEV-infected rats, reduced disease severity, reversed electrophysiological and histological abnormalities, significantly reduced circulating proinflammatory cytokine levels, inhibited Th1 and Th17 cell proliferation, and suppressed the infiltration of inflammatory CD4 + cells into the sciatic nerve. It also maintained the peripheral nerve-blood barrier without causing severe clinical side effects. In terms of the potential mechanisms, ASM was found to participate in immune cell differentiation and to activate immune cells, thereby exerting proinflammatory effects. Therefore, immunoglobulin is a FIASMA that reduces abnormal immune responses and thus targets the ASM/ceramide system to treat peripheral neuropathy caused by JEV infection.

Autonomous robotic system for the assisted immediate placement of a maxillary anterior implant: A clinical report.

Precise reproduction of the preoperatively designed 3-dimensional (3D) implant position is key to seating a prefabricated restoration and restoring esthetics. Static and dynamic computer-aided implant surgery (CAIS) based on the fusion of 3D imaging files have been used to improve implant accuracy. However, both techniques have shortcomings that can be remedied by a robotic system. This clinical report describes the immediate placement of an implant in the anterior esthetic zone by using an autonomous dental implant robotic system (ADIR).

Construction of TiO2/CuPc Heterojunctions for the Efficient Photocatalytic Reduction of CO2 with Water.

Utilizing solar energy for photocatalytic CO2 reduction is an attractive research field because of its convenience, safety, and practicality. The selection of an appropriate photocatalyst is the key to achieve efficient CO2 reduction. Herein, we report the synthesis of TiO2/CuPc heterojunctions by compositing CuPc with TiO2 microspheres via a hydroxyl-induced self-assembly process. The experimental investigations demonstrated that the optimal TiO2/0.5CuPc photocatalyst exhibited a significantly enhanced CO2 photoreduction rate up to 32.4 µmol·g-1·h-1 under 300 W xenon lamp irradiation, which was 3.7 times that of the TiO2 microspheres alone. The results of photoelectrochemical experiments indicated that the construction of the heterojunctions by introducing CuPc effectively promoted the separation and transport of photogenerated carriers, thus enhancing the catalytic effect of the photocatalyst.

Peripheral nerve injury associated with JEV infection in high endemic regions, 2016-2020: a multicenter retrospective study in China.

Previously, we reported a cohort of Japanese encephalitis (JE) patients with Guillain-Barré syndrome. However, the evidence linking Japanese encephalitis virus (JEV) infection and peripheral nerve injury (PNI) remains limited, especially the epidemiology, clinical presentation, diagnosis, treatment, and outcome significantly differ from traditional JE. We performed a retrospective and multicenter study of 1626 patients with JE recorded in the surveillance system of the Chinese Center for Disease Control and Prevention, spanning the years 2016-2020. Cases were classified into type 1 and type 2 JE based on whether the JE was combined with PNI or not. A comparative analysis was conducted on demographic characteristics, clinical manifestations, imaging findings, electromyography data, laboratory results, and treatment outcomes. Among 1626 laboratory confirmed JE patients, 230 (14%) were type 2 mainly located along the Yellow River in northwest China. In addition to fever, headache, and disturbance of consciousness, type 2 patients experienced acute flaccid paralysis of the limbs, as well as severe respiratory muscle paralysis. These patients presented a greater mean length of stay in hospital (children, 22 years [range, 1-34]; adults, 25 years [range, 0-183]) and intensive care unit (children, 16 years [range, 1-30]; adults, 17 years [range, 0-102]). The mortality rate was higher in type 2 patients (36/230 [16%]) compared to type 1 (67/1396 [5%]). The clinical classification of the diagnosis of JE may play a crucial role in developing a rational treatment strategy, thereby mitigating the severity of the disease and potentially reducing disability and mortality rates among patients.

Maxillary sinus floor elevation for implant placement assisted by an autonomous dental implant robotic system: A clinical report.

Precise implant placement is key to ensuring the success of dental implant surgery. Implant robotic systems have been increasingly adopted for clinical procedures because of their accuracy. Maxillary sinus floor elevation with the Disk-up Sinus Reamer (DSR) may be an effective solution for inadequate posterior maxillary bone height. This clinical treatment combined with an autonomous implant robot with DSR for maxillary sinus floor elevation with simultaneous dental implant surgery may be suitable for clinical practice.

Untimely surgery for stent-fracture-related death after transjugular intrahepatic portosystemic shunt: a case report.

Transjugular intrahepatic portosystemic shunt (TIPS) is a life-saving procedure for patients with severe portal hypertension and persistent variceal bleeding. Stent fracture is a rare and severe complication; however, its cause and mechanisms remain poorly defined. This case helps understand the factors contributing to its occurrence, complications, and subsequent poor outcomes. A 63-year-old male was presented with ruptured bare stent after a TIPS procedure. The upper edge of the bare stent was ruptured, and its fraction subsequently migrated to the entrance of the right atrium. Meanwhile, a mural thrombus was formed in the inferior vena cava. A surgery for the removal of free fracture was planned for preventing the form of pulmonary embolism. Before the surgery, the fracture was shifted to the right inferior pulmonary artery. Therefore, the surgery was canceled for further evaluation. Then, hematemesis suddenly occurred with a high possibility of variceal bleeding and/or gastric ulcer bleeding. Despite comprehensive treatments, the patient symptoms were still worsened with the development of chest tightness, shortness of breath, severe hypoxia, and heart failure. Finally, the patient succumbed to systemic multiorgan failure and death. Taken together, a ruptured unstable stent should be removed as early as the patient is hemodynamically stable, as it is difficult to balance between hemostasis therapy and anticoagulation treatment in patients with liver-cirrhosis-related severe portal hypertension. Physicians should be on high alert of the potential complications of bare stent rapture after TIPS.

Ruptured TIPS stent with a fatal consequence Unstable stent rupture is a life-threatening complication of TIPS and severely complicates the treatment of gastric ulcer bleeding. Early removal of the ruptured stent is necessary to prevent further complications.

Efficacy of traditional Chinese medicine versus angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and their combinations in the treatment of IgA nephropathy: a systematic review and network meta-analysis.

Background: IgA nephropathy (IgAN), a condition posing a significant threat to public health, currently lacks a specific treatment protocol. Research has underscored the potential benefits of traditional Chinese medicine (TCM) for treating IgAN. Nevertheless, the effectiveness of various intervention strategies, such as combining TCM with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), lacks a comprehensive systematic comparison. Therefore, this study aimed to conduct a network meta-analysis to assess the clinical efficacy of ACEIs, ARBs, TCM, and their combinations in treating IgAN to offer novel insights and approaches for the clinical management of IgAN. Methods: A systematic review conducted until November 2023 included relevant literature from databases such as PubMed, Embase, Cochrane, Web of Science, Scopus, CNKI, and Wanfang. Two independent researchers screened and assessed the data for quality. Network and traditional meta-analyses were performed using Stata 18.0 and RevMan 5.3 software, respectively. Outcome measures included 24-h urinary protein quantification (24 hpro), estimated glomerular filtration rate (eGFR), serum creatinine (Scr), blood urea nitrogen (BUN), and adverse event incidence rates (ADRs). Forest plots, cumulative ranking probability curves (SUCRA), and funnel plots generated using Stata 18.0 facilitated a comprehensive analysis of intervention strategies' efficacy and safety. Results: This study included 72 randomized controlled trials, seven interventions, and 7,030 patients. Comparative analysis revealed that ACEI + TCM, ARB + TCM combination therapy, and TCM monotherapy significantly reduced the levels of 24 hpro, eGFR, Scr, and BUN compared to other treatment modalities (p < 0.05). TCM monotherapy demonstrated the most favorable efficacy in reducing eGFR levels (SUCRAs: 78%), whereas the combination of ARB + TCM reduced Scr, 24 hpro, and BUN levels (SUCRAs: 85.7%, 95.2%, and 87.6%, respectively), suggesting that ARB + TCM may represent the optimal intervention strategy. No statistically significant differences were observed among the various treatment strategies in terms of ADR (p > 0.05). Conclusion: The combination of ACEI or ARB with TCM demonstrated superior efficacy compared to ACEI/ARB monotherapy in the treatment of IgAN without any significant ADRs. Therefore, combination therapies can be used to enhance therapeutic outcomes based on individual patient circumstances, highlighting the use of TCM as a widely applicable approach in clinical practice. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023476674.

A type I and type II chemical biology toolbox to overcome the hypoxic tumour microenvironment for photodynamic therapy.

Photodynamic therapy (PDT) is a minimally invasive therapeutic modality employed for the treatment of various types of cancers, localized infections, and other diseases. Upon illumination, the photo-excited photosensitizer generates singlet oxygen and other reactive species, thereby inducing cytotoxicity in the target cells. The hypoxic tumour microenvironment (TME), however, poses a limitation on the supply of oxygen in tumour tissues. Moreover, under such conditions, tumour metastasis and drug resistance frequently occur, further compromising the efficacy of PDT in combating tumours. Traditionally, type I photosensitizers with lower oxygen consumption demonstrate significant potential in overcoming hypoxic environments and play a crucial role in determining the therapeutic efficacy of PDT because type I photosensitizers can generate highly cytotoxic free radicals. In comparison, type II photosensitizers exhibit high oxygen dependence. The rate of reactive oxygen species (ROS) generation in the type II process is significantly higher than that in the type I process. Thus, the efficiency and selectivity of PDT depend on the properties of the photosensitizer. Here, the recent development and application of type I and type II photosensitizers, mainly in the past year, are summarized. The design methods, electronic structures, photophysical properties, lipophilic properties, electric charge, and other molecular characteristics of these photosensitizers are discussed in detail. These modifications alter the microstructure of photosensitizers and directly impact the results of PDT. The main content of this paper will have a positive promoting and inspiring effect on the future development of PDT.

Dissolution and regeneration of starch in hydroxyl-functionalized ionic liquid aqueous solution.

There have been continuous quests for suitable solvents for starch, given the importance of effective starch dissolution in its modification and subsequent materials production. In light of this, the potential of hydroxyl-functionalized ionic liquid (IL) as a promising solvent for starch was investigated. Within this study, a hydroxyl-functionalized IL 1-(2,3-dihydroxypropyl)-3-methylimidazole chloride ([Dhpmim][Cl]) was synthesized, and the dissolution of starch in this IL and its aqueous solutions was examined. Starch (5.35 wt%) was completely dissolved in [Dhpmim][Cl] within 2 h at 100 °C. The solubility of starch in [Dhpmim][Cl]-water mixtures initially increased and then decreased with rising water content. The optimal ratio was found to be 1:9 (wt/wt) water:[Dhpmim][Cl], achieving the highest solubility at 9.28 wt%. Density functional theory (DFT) simulations elucidated the possible interactions between starch and solvents. After dissolution and regeneration in the 1:9 water:[Dhpmim][Cl] mixture, starch showed no discernible change in the molecular structure, with no derivatization reaction observed. Regenerated starch exhibited a transformation in crystalline structure from A-type to V-type, and its relative crystallinity (12.4 %) was lower than that of native starch (25.2 %), resulting in decreased thermal stability. This study suggests that the hydroxyl-functionalized IL, [Dhpmim][Cl], and its aqueous solutions serve as effective solvents for starch dissolution.

Aerosol inhalation of inflammatory cells-targeted dendrimer-dexamethasone conjugate for efficient allergic asthma therapy.

Allergic asthma (AA) is a common breathing disorder clinically characterized by the high occurrence of acute and continuous inflammation. However, the current treatment options for AA are lacking in effectiveness and diversity. In this study, we determined that the cell membrane receptor of gamma-glutamyl transferase (GGT) was highly overexpressed on the inflammatory cells that infiltrate the pulmonary tissues in AA cases. Therefore, we developed a GGT-specific dendrimer-dexamethasone conjugate (GSHDDC) that could be administered via aerosol inhalation to treat AA in a rapid and sustained manner. The GSHDDC was fabricated by the covalent attachment of 6-hydroxyhexyl acrylate-modified dexamethasone to polyamidoamine dendrimers via a carbonic ester linkage and the amino Michael addition, followed by the surface modification of the dendrimers with the GGT substrate of glutathione. After aerosol inhalation by the AA mice, the small particle-sized GSHDDC could easily diffuse into pulmonary alveoli and touch with the inflammatory cells via the glutathione ligand/GGT receptor-mediated recognition. The overexpressed GGT on the surface of inflammatory cells then triggers the gamma-glutamyl transfer reactions of glutathione to generate positively charged primary amines, thereby inducing rapid cationization-mediated cellular endocytosis into the inflammatory cells. The dexamethasone was gradually released by the intracellular enzyme hydrolysis, enabling sustained anti-inflammatory effects (e.g., reducing eosinophil infiltration, decreasing the levels of inflammatory factors) in the ovalbumin-induced AA mice. This study demonstrates the effectiveness of an inhalational and active inflammatory cells-targeted dendrimer-dexamethasone conjugate for efficient AA therapy.