Indomethacin Does Not Reduce Post-ERCP Pancreatitis in High-Risk Patients Receiving Pancreatic Stenting.

BACKGROUND: Rectal indomethacin reduces pancreatitis following endoscopic retrograde cholangiopancreatography (ERCP). However, there is insufficient evidence regarding its added benefits in patients already receiving prophylactic pancreatic stenting. Our goal was to evaluate the impact of indomethacin in high-risk patients undergoing pancreatic stenting. METHODS: A cohort study was conducted on all patients who underwent the rescue cannulation technique for challenging bile duct cannulation (selected high-risk patients). Patients were split into two groups based on the prophylaxis method for post-ERCP pancreatitis (PEP): one receiving a combination of indomethacin and pancreatic stenting, while the other received pancreatic stenting alone. Comparative analyses were carried out on PEP, hyperamylasemia, gastrointestinal bleeding, and postoperative hospital stay among post-ERCP pancreatitis patients. RESULTS: Between November 2017 and May 2023, a total of 607 patients with native papillae were enrolled, with 140 grouped into the indomethacin plus stent group and 467 into the stent alone group. The overall PEP rate was 4.4% in the entire cohort, with no statistical differences observed between the groups in terms of PEP rates (P = 0.407), mild PEP (P = 0.340), moderate to severe PEP (P = 1.000), hyperamylasemia (P = 0.543), gastrointestinal bleeding (P = 0.392), and postoperative hospital stay (P = 0.521). Furthermore, sensitivity analysis using multivariable analysis also validated these findings. CONCLUSIONS: Indomethacin did not reduce the incidence or severity of PEP in high-risk patients who routinely received prophylactic pancreatic stent placement. Therefore, the additional administration of rectal indomethacin to further mitigate PEP appears to be not necessary.

Inhibition of thioredoxin reductase and upregulation of apoptosis genes for effective anti-tumor sono-chemotherapy using a meso-organosilica nanomedicine.

The thioredoxin system is involved in cancer development and therefore is a promising target for cancer chemotherapy. Thioredoxin reductase (TrxR) is a key component of the thioredoxin (Trx) system, and is overexpressed in many cancers to inhibit apoptosis-related proteins. Alternatively, inhibition of thioredoxin reductase and upregulation of apoptosis factors provide a therapeutic strategy for anti-tumor treatment. In this study, an ultrasound-activatable meso-organosilica nanomedicine was prepared by integrating chloroquine (CQ) into hollow mesoporous organosilica (CQ@MOS). The meso-organosilica nanomedicine can inhibit the activity of thioredoxin reductase, elevate cellular reactive oxygen species (ROS) levels, upregulate the pro-apoptotic factors in the c-Jun N-terminal kinase (JNK) apoptosis pathway and induce autophagy inhibition, further resulting in mitochondrial membrane potential (MMP) depolarization and cellular ATP content decrease, ultimately causing significant damage to tumor cells. Moreover, CQ@MOS can efficiently deliver chloroquine into cancer cells and promote an enhanced sonodynamic effect for effective anti-tumor chemotherapy and sonodynamic therapy. This study may enlighten us on a new anti-tumor strategy and suggest its promising applications in cancer treatments.

Computer-aided investigation of Traditional Chinese Medicine mechanisms: A case study of San-Ao decoction in asthma treatment.

The San-Ao Decoction (SAD) is a well-known Traditional Chinese Medicine (TCM) formula used to alleviate respiratory symptoms, including asthma. However, its precise mechanisms of action have remained largely unknown. In this study, we utilized computer-aided approaches to explore these mechanisms. Firstly, we conducted a comprehensive analysis of the chemical composition of SAD, which allowed us to identify the 28 main ingredients. Then, we employed computer simulations to investigate the potential active ingredients of SAD and the corresponding binding sites of transient receptor potential vanilloid 1 (TRPV1). The simulations revealed that D509 and D647 were the potential binding sites for TRPV1. Notably, molecular dynamics (MD) studies indicated that site D509 may function as an allosteric site of TRPV1. Furthermore, to validate the computer-aided predictions, we performed experimental studies, including in vitro and in vivo assays. The results of these experiments confirmed the predictions made by our computational models, providing further evidence for the mechanisms of action of San-Ao Decoction in asthma treatment. Our findings demonstrated that: i) D509 and D647 of TRPV1 are the key binding sites for the main ingredients of SAD; ii) SAD or its main ingredients significantly reduce the influx of Ca2+ through TRPV1, following the TCM principle of "Jun, Chen, Zuo, Shi"; iii) SAD shows efficiency in comprehensive in vivo validation. In conclusion, our computer-aided investigation of San-Ao Decoction in asthma treatment has provided valuable insights into the therapeutic mechanisms of this TCM formula. The combination of computational analysis and experimental validation has proven effective in enhancing our understanding of TCM and may pave the way for future discoveries in the field.

Organophosphate Level Evaluation for the Poisoning Treatment by Enzyme Activation Regeneration Strategy with Oxime-Functionalized ZIF-8 Nanoparticles.

In this work, two nanometal-organic frameworks (NMOFs) of ZIF-8-1 and ZIF-8-2 were designed and synthesized with a "missing linker" defects strategy by using Oxime-1 and Oxime-2 as coligands, respectively. ZIF-8-2 exhibited an excellent performance in comparison to that of ZIF-8-1 in activating and regenerating the activity of BChE suppressed by demeton-S-methyl (DSM) and could rapidly detoxify DSM in poisoned serum samples within 24 min. Additionally, the synthesized fluorescence probe of IND-BChE with high quantum yields, large Stokes shifts, and superior water solubility could be used for the detection of both butyrylcholinesterase (BChE) and DSM in a lower LOD of 0.63 mU/mL (BChE) and 0.086 µg/mL (DSM). By the difference in fluorescent intensity of IND-BChE with and without ZIF-8-2, a highly linear relationship of IND-BChE with DSM concentration was found (R2 = 0.9889), and the LOD was 0.073 µg/mL. In addition, an intelligent detection platform of ZIF-8-2@IND-BChE@agarose hydrogel combined with a smartphone formed a point-of-care test for DSM -poisoned serum samples and also realized satisfactory results. Unlike other detection methods of nerve agents, this assay first combined an NMOF reactivator for detoxification and detection of BChE enzyme activity and then quantification of OP nerve agents, which was of great significance in treatment of organophosphate poisoning.

Simple method for visual detection of nitrite using fluorescence and colorimetry by poly (tannic acid) nanoparticles.

The nitration reaction of nitrite and phenolic substances was first used to identify and detect NO2- by taking fluorescent poly (tannic acid) nanoparticles (FPTA NPs) as sensing platform. With the low cost, good biodegradable and convenient water-soluble FPTA NPs, a fluorescent and colorimetric dual modes detecting assay was realized. In fluorescent mode, the linear detection range of NO2- was 0-36 µM, the LOD was as low as 3.03 nM, and the response time was 90 s. In colorimetric mode, the linear detection range of NO2- was 0-46 µM, and the LOD was as low as 27 nM. Besides, a smartphone with FPTA NPs@ agarose hydrogel formed a portable detection platform to test the fluorescent and visible color changes of FPTA NPs for NO2- sensing as well as for accurate visualization and quantitative detection of NO2- in actual water and food samples.

Ultrasensitivity Detecting AChE through "Covalent Assembly" and Signal Amplification Strategic Approaches and Applied to Screen Its Inhibitor.

An ultrasensitivity detecting assay for acetylcholinesterase (AChE) activity was developed based on "covalent assembly" and signal amplification strategic approaches. After hydrolyzing thioacetylcholine by AChE and participation of thiol in a self-inducing cascade accelerated by the Meldrum acid derivatives of 2-[bis(methylthio) methylene] malonitrile (CA-2), mercaptans triggered an intramolecular cyclization assembly by the probe of 2-(2,2-dicyanovinyl)-5-(diethylamino) phenyl 2,4-dinitrobenzenesulfonate (Sd-I) to produce strong fluorescence. The limit of detection for AChE activity was as low as 0.0048 mU/mL. The detection system also had a good detecting effect on AChE activity in human serum and could also be used to screen its inhibitors. By constructing a Sd-I@agarose hydrogel with a smartphone, a point-of-care detection of AChE activity was achieved again.

Effects of Houpo Mahuang Decoction on serum metabolism and TRPV1/Ca2+/TJs in asthma.

ETHNOPHARMACOLOGICAL RELEVANCE: Houpo Mahuang Decoction (HPMHD is one of the classic traditional Chinese prescriptions that has been used in the treatment of asthma. The therapeutic effects and mechanism of HPMHD in aggravated asthma remain to be explored, especially from the perspective of metabolomics and Transient Receptor Potential Vanilloid-1 (TRPV1)/Ca2+/Tight junction (TJ) regulation. AIM OF THE STUDY: To investigate the therapeutic and metabolic regulatory effects and the underlying mechanism of HPMHD in asthmatic rats. MATERIALS AND METHODS: The asthmatic rats were administered with the corresponding HPMHD (at dosages of 5.54, 11.07, 22.14 mg/kg). Then inflammatory cells in peripheral blood and bronchoalveolar lavage fluid (BALF) were counted, the levels of interleukin (IL)-4 and IL-13 in BALF were measured, and the changes in enhanced pause (Penh) and pathological damage of lung tissues were also detected to evaluate the protective effects of HPMHD. The serum metabolic profile of HPMHD in asthmatic rats was explored using Ultra-High-Performance Liquid Chromatography-mass spectrometer (UHPLC-MS), and the regulatory effects on TRPV1 and TJs of HPMHD in asthmatic rats were detected by Western blotting analysis. In vitro, 16HBE cells were stimulated with IL-4 plus SO2 derivatives and then administered HPMHD. The intracellular Ca2+ regulated by TRPV1, and the expression levels of TRPV1 and TJ proteins (TJs) were then detected by calcium imaging and Western blotting. The effects were verified by inhibition of TRPV1 and in short hairpin RNA (shRNA)-mediated TRPV1 silencing cells. RESULTS: HPMHD significantly attenuated the airway inflammation of asthmatic rats, and reduced the levels of inflammatory cells in peripheral blood and BALF as well as the levels of IL-4 plus IL-13 in BALF. In addition, the airway hyperresponsiveness and lung pathological damage were alleviated. Serum metabolomic analysis showed that 31 metabolites were differentially expressed among the normal saline-, model-, and HPMHD-treated rats. Pathway enrichment analysis showed that the metabolites were involved in 45 pathways, among which, TJs regulation-relevant pathway was associated with the Ca2+ concentration change mediated by the TRP Vanilloid channel. In vivo and in vitro experiments indicated that HPMHD reduced the concentration of intracellular Ca2+ via suppressing the expression and activation of TRPV1, increased the expression of ZO-1, Occludin, and Claudin-3, and protected the integrity of TJs. CONCLUSION: The current study indicates that HPMHD alleviates rat asthma and participates in the regulation of serum metabolism. The anti-asthma effects of HPMHD might be related to the protection of TJs by inhibiting the intracellular Ca2+ concentration via TRPV1.

[Effect of Maxing Shigan Decoction and dissembled prescriptions against airway inflammation in RSV-aggravated asthma and mechanism of regulating TRPV1].

This study investigated the effect of Maxing Shigan Decoction(MXSGD) and its disassembled prescriptions against the airway inflammation in respiratory syncytial virus(RSV)-aggravated asthma and the regulation of transient receptor potential vanilloid-1(TRPV1). To be specific, ovalbumin(OVA) and RSV were used to induce aggravated asthma in mice(female, C57BL/6). Then the model mice were intervened by MXSGD and the disassembled prescriptions. The eosinophil(EOS) in peripheral blood, inflammatory cells in bronchoalveolar lavage fluid(BALF), enhanced pause(Penh) variation, and lung pathological damage in each group were observed, and the changes of interleukin(IL)-4, IL-13, substance P(SP), and prostaglandin E2(PGE2) in BALF were mea-sured by enzyme-linked immunosorbent assay(ELISA). Quantitative real time polymerase chain reaction(qPCR) and Western blot were used to detect mRNA and protein of TRPV1 in mouse lung tissue. In the in vitro experiment, 16 HBE cells were stimulated with IL-4 and RSV. Then the changes of TRPV1 expression after the intervention with the serum containing MXSGD and its disassembled prescriptions were observed. Besides, the intracellular Ca~(2+) level after the stimulation with TRPV1 agonist was evaluated. The results showed that the mice in the model group had obvious asthma phenotype, the levels of various inflammatory cells in the peripheral blood and BALF and Penh were significantly increased(P<0.05, P<0.01), and the lung tissue was severely damaged compared with the control group. Compared with the model group, the levels of EOS in the peripheral blood and BALF were significantly decreased in the MXSGD group, the SG group and the MXC group(P<0.05, P<0.01). The levels of WBC and neutrophils in BALF were significantly decreased in the MXSGD group and SG group(P<0.01), the levels of neutrophils in BALF were decreased in the MXC group(P<0.05). The improvement effect of the MXGSD on the level of inflammatory cells in peripheral blood and BALF was better than that of two disassembled groups(P<0.05, P<0.01). After 50 mg·mL~(-1) acetylcholine chloride stimulation, the Penh values of the MXSGD group and the MXC group significantly decreased(P<0.01), and the Penh value of the SG group decreased(P<0.05). The levels of IL-4, IL-13, PGE2 and SP in BALF could be significantly decreased in the MXSGD group(P<0.05, P<0.01), the levels of IL-13 and PGE2 in BALF could be decreased in the MXC group(P<0.05, P<0.01), and the levels of IL-13, PGE2 and SP in BALF could be decreased in the SG group(P<0.05, P<0.01). MXSGD could down-regulate the protein and mRNA expression of TRPV1 in lung tissue(P<0.05, P<0.01). The serum containing MXSGD and its disassembled prescriptions could down-regulate TRPV1 expression in 16 HBE cells stimulated by IL-4 combined with RSV and inhibit the inward flow of Ca~(2+) induced by TRPV1 agonist, especially the serum containing MXSGD which showed better effect than the serum containing disassembled ones(P<0.05). In vivo and in vitro experiments verified the protective effect of MXSGD and its disassembled prescriptions against airway inflammation in RSV-exacerbated asthma, the whole decoction thus possessed synergy in treating asthma, with better performance than the dissembled prescriptions. Different groups of prescription had made contributions in improving airway hyperresponsiveness, anti-allergy and anti-inflammation. The mechanism is the likelihood that it regulates TRPV1 channel and levels of related inflammatory mediators.

Integrative Functional Transcriptomic Analyses Implicate Shared Molecular Circuits in Sensorineural Hearing Loss.

Sensorineural hearing loss (SNHL) is referred to as the most common type of hearing loss and typically occurs when the inner ear or the auditory nerve is damaged. Aging, noise exposure, and ototoxic drugs represent three main causes of SNHL, leading to substantial similarities in pathophysiological characteristics of cochlear degeneration. Although the common molecular mechanisms are widely assumed to underlie these similarities, its validity lacks systematic examination. To address this question, we generated three SNHL mouse models from aging, noise exposure, and cisplatin ototoxicity, respectively. Through constructing gene co-expression networks for the cochlear transcriptome data across different hearing-damaged stages, the three models are found to significantly correlate with each other in multiple gene co-expression modules that implicate distinct biological functions, including apoptosis, immune, inflammation, and ion transport. Bioinformatics analyses reveal several potential hub regulators, such as IL1B and CCL2, both of which are verified to contribute to apoptosis accompanied by the increase of (ROS) in in vitro model system. Our findings disentangle the shared molecular circuits across different types of SNHL, providing potential targets for the broad effective therapeutic agents in SNHL.

The effect of Ma-Xin-Gan-Shi decoction on asthma exacerbated by respiratory syncytial virus through regulating TRPV1 channel.

ETHNOPHARMACOLOGICAL RELEVANCE: The incidence and mortality of bronchial asthma are increasing, and respiratory syncytial virus (RSV) is widely regarded as the common cause of clinical exacerbation of asthma. Ma-Xing-Gan-Shi decoction (MXGSD), a classic traditional Chinese medicine prescription, is well-known for treating respiratory diseases, while the mechanism of effecting on RSV-exacerbated asthma remains to be explored. AIM OF THE STUDY: In this study, we investigated the mechanism by which MXGSD exerts a protective effect on asthma exacerbated by RSV in vivo and in vitro. MATERIALS AND METHODS: MXGSD is composed of four Chinese medicine, including Ephedra intermedia Schrenk & C.A.Mey. (herbaceous stem, 27g), Prunus armeniaca L. (dry seed, 27g), Glycyrrhiza uralensis Fisch. (radix and rhizome, 18g), and Gypsum fibrosum (main component: CaSO4·2H2O, 54g). In the present study, the exacerbated asthmatic mice model with the treatment of OVA plus RSV was replicated, and accompanied by the TMT proteomic analysis and further experimental investigations. Then, the protective effect of MXGSD (13.2, 6.6, 3.3 g/kg/d, 7d) on the mice treated by OVA plus RSV, and the mechanism of regulating TRPV1 was explored. In addition, the intracellular Ca2+ concentration of 16HBE cells pretreated with MXGSD medicated serum was also tested after stimulation with the TRPV1 agonist capsaicin. RESULTS: The results suggested that MXGSD could reduce the levels of inflammation cells, airway hyperresponsiveness, and pathological damage of lung tissue. TMT quantitative proteomics analysis and further experimental exploration revealed that MXGSD could reduce the levels of IL-4, IL-13, PGE2, and SP in BAL and down-regulate the expression of TRPV1 mRNA and protein in lung tissue. Furthermore, 16HBE cells stimulated by capsaicin showed an increased intracellular Ca2+ concentration, while the pretreatment of MXGSD medicated serum could reduce it. CONCLUSION: MSGSD showed a protective effect on RSV-exacerbated asthma, which may be related to its regulation of TRPV1 expression and reduction of Th2 cytokines and neurogenic inflammatory mediators. It may provide an objective basis and reference for the clinical application of MXGSD.

Rapid detection of multiple pathogens by the combined loop-mediated isothermal amplification technology and microfluidic chip technology.

BACKGROUND: A rapid detection system for multiple pathogens that combines loop-mediated isothermal amplification (LAMP) technology and microfluidic chip technology was established. METHODS: Primers were designed for the specific conservative genes of the multiple pathogens. A rapid detection method for multiple pathogens based on LAMP technology was established using the primer screening and optimization of reaction conditions. The microfluidic chip was designed. manufactured, and combined with the LAMP method for detection pathogenic bacteria as detected by a chip detector. After this, the detection limit and anti-interference ability of the chip were evaluated, and the accuracy of chip was verified by clinical samples. RESULTS: A rapid microfluidic detection system for Staphylococcus aureus, Escherichia coli, Pneumoniae klebsiella, Shigella, Methicillin-resistant Staphylococcus Aureus (MRSA) and Candida albicans was established. The detection limits of the 6 strains above were 6.95, 44.6, 3.89, 15.33, 16.45, and 463 pg/µL, respectively; there was no cross-reaction with the other 15 strains; analysis of ROC curve showed the best cut-off values for the 6 strains are 38.5, 21.25, 31.5, 36.5, 22.5 and 33.75 respectively and the area under the curve for the 6 strains was 0.91, 0.91, 0.83, 0.97, 0.96, and 0.9, respectively, as analyzed by receiver operating characteristic curve (ROC). A total of 278 clinical samples collected including blood, urine, sputum and drainage fluid were analyzed, and the total coincidence rates were 0.91, 0.83, 0.75, 0.99, 0.92 and 0.76, respectively. CONCLUSIONS: The establishment of microfluidic detection chips for multiple pathogen types can be used for the rapid detection of bacteria and may be particularly useful in environments with the limited equipment and personnel, such as infection sites, grassroots hospitals, disaster area rescue, etc.

Phenotypic and genomic adaptations to the extremely high elevation in plateau zokor (Myospalax baileyi).

The evolutionary outcomes of high elevation adaptation have been extensively described. However, whether widely distributed high elevation endemic animals adopt uniform mechanisms during adaptation to different elevational environments remains unknown, especially with respect to extreme high elevation environments. To explore this, we analysed the phenotypic and genomic data of seven populations of plateau zokor (Myospalax baileyi) along elevations ranging from 2,700 to 4,300 m. Based on whole-genome sequencing data and demographic reconstruction of the evolutionary history, we show that two populations of plateau zokor living at elevations exceeding 3,700 m diverged from other populations nearly 10,000 years ago. Further, phenotypic comparisons reveal stress-dependent adaptation, as two populations living at elevations exceeding 3,700 m have elevated ratios of heart mass to body mass relative to other populations, and the highest population (4,300 m) displays alterations in erythrocytes. Correspondingly, genomic analysis of selective sweeps indicates that positive selection might contribute to the observed phenotypic alterations in these two extremely high elevation populations, with the adaptive cardiovascular phenotypes of both populations possibly evolving under the functional constrains of their common ancestral population. Taken together, phenotypic and genomic evidence demonstrates that heterogeneous stressors impact adaptations to extreme elevations and reveals stress-dependent and genetically constrained adaptation to hypoxia, collectively providing new insights into the high elevation adaptation.

Cochlear hair cells of echolocating bats are immune to intense noise.

Exposure to intense noise can damage cochlear hair cells, leading to hearing loss in mammals. To avoid this constraint, most mammals have evolved in relatively quiet environments. Echolocating bats, however, are naturally exposed to continuous intense sounds from their own and neighboring sonar emissions for maintaining sonar directionality and range. Here, we propose the presence of intense noise resistance in cochlear hair cells of echolocating bats against noise-induced hearing loss (NIHL). To test this hypothesis, we performed noise exposure experiments for laboratory mice, one nonecholocating bat species, and five echolocating bat species. Contrary to nonecholocating fruit bats and mice, the hearing and the cochlear hair cells of echolocating bats remained unimpaired after continuous intense noise exposure. The comparative analyses of cochleae transcriptomic data showed that several genes protecting cochlear hair cells from intense sounds were overexpressed in echolocating bats. Particularly, the experimental examinations revealed that ISL1 overexpression significantly improved the survival of cochlear hair cells. Our findings support the existence of protective effects in cochlear hair cells of echolocating bats against intense noises, which provides new insight into understanding the relationship between cochlear hair cells and intense noises, and preventing or ameliorating NIHL in mammals.

Depression of Pyroptosis by Inhibiting Caspase-1 Activation Improves Neurological Outcomes of Kernicterus Model Rats.

Kernicterus is a severe complication of extreme neonatal hyperbilirubinemia. Prolonged exposure to high-level unconjugated bilirubin (UCB) directly damages brain tissue. Neuroinflammation is believed to contribute to UCB-induced neurotoxicity. Pyroptosis has been as a highly inflammatory form of programmed cell death. Therefore, this study aimed to explore whether pyroptosis was involved in the pathogenesis of UCB neurotoxicity in kernicterus model rats. VX-765, a specific inhibitor of caspase-1, was intraperitoneally administered to the model rats to observe its effects on the short-term and long-term outcomes of the model animals at the molecular, cellular, morphological, and behavioral levels. The results indicated that UCB significantly induced the activation of caspase-1 and gasdermin D(GSDMD), and VX-765 inhibited caspase-1-GSDMD pathway. Compared with those of the UCB group and the vehicle+UCB group, VX-765-treated rats released lower levels of IL-1ß and IL-18. Furthermore, H&E and TUNEL staining showed that nerve cells in the VX-765-treated group were better preserved and had less DNA fragmentation. Most importantly, VX-765 improved both the short-term and long-term neurological functions of kernicterus model rats. This study demonstrated that pyroptosis was involved in the pathogenesis of kernicterus through caspase-1 activation, which could be inhibited by VX-765, exerting a neuroprotective effect in kernicterus model rats.

Effects of cigarette smoke on the aggravation of ovalbumin-induced asthma and the expressions of TRPA1 and tight junctions in mice.

The occurrence of asthma is closely related to environmental factors such as cigarette smoke (CS), one of the common risk factors. Environmental stimuli have the potential to activate transient receptor potential ankyrin 1 (TRPA1) and cause or aggravate asthma. The destruction of tight junctions (TJs) between airway epithelial cells by environmental stimuli in asthma has been researched. It is worth exploring whether CS can injury TJs and aggravate asthma by activating TRPA1. The objective of this study was to investigate the aggravation of CS on ovalbumin (OVA)-induced asthma related phenotypes and TJs expression in mice, and to explore the relationship between TRPA1 and the expression of TJs protein. Female wild type (WT) C57BL/6 mice, induced by OVA, CS and OVA plus CS (OVA + CS) respectively, were used to establish a 42-day asthma model, and mice with TRPA1 knockout (TRPA1-/-) were treated in the same way. This study detected the number of inflammatory cells in peripheral blood and bronchoalveolar lavage fluid (BALF), the levels of IL-4, IL-5, IL-13 in BALF, enhanced pause (Penh) of lung function, pathological changes and the gene and protein expressions of TRPA1 and TJs (including ZO-1, Occludin and Claudin-2) in lung tissues. Compared with normal saline (NS) group, WT mice in the OVA group and OVA + CS group were significantly higher in asthma related phenotypes. The WT-OVA + CS group also showed higher Penh value, levels of IL-5 and IL-13 in BALF and lung tissue injury scores when compared with the WT-OVA group and WT-CS group. However, WT-OVA + CS group mice had significantly larger number of neutrophils in BALF than the WT-OVA group, and had larger number of eosinophils in peripheral blood and higher levels of IL-4 in BALF than the WT-CS group. Meanwhile, compared with the WT-NS group, the expressions of TRPA1 and Claudin-2 in lung tissues increased in other three groups while their expressions of ZO-1 and Occludin decreased, among which, the WT-OVA + CS group showed more remarkable changes. Compared with the WT-OVA + CS group, mice in the TRPA1-/--OVA + CS showed a significant decrease in the number of inflammatory cells, levels of IL-4, IL-5 and IL-13 in BALF, Penh value and lung tissue injury score, and a downregulation of Claudin-2 expression while an upregulation of ZO-1 and Occludin expressions. In addition, the airway inflammation and injury, and the expressions of ZO-1, Occluding and Claudin-2 expressions were found with no statistic differences between TRPA1-/--OVA group and TRPA1-/--OVA + CS group. These results suggest that CS has aggravated the airway inflammation, pathological damage and destruction of TJs in airway epithelium of OVA-induced asthmatic mice, the processes of which are related to the increase of TRPA1 expression.

Tb3+-Doped Ag-MOFs for fluorescent detection of formaldehyde in a novel smartphone platform and its removal applications in milk products and wastewater.

As one kind of reactive carbonyl species (RCS), formaldehyde (FA) with a high concentration could be extremely toxic to living bodies as well as the environment. This paper reports a three-dimensional (3D) Tb3+@Ag-MOFs-based fluorescent probe for fast sensing of FA, which uses a novel turn-on mechanism based on the luminescence induced by Tb3+. The MOF sensor shows broad dynamic ranges of 0.1-1 mM for FA with the detection limit of 1.9 µM. For online and real-time detection of FA, a portable smartphone platform was employed to analyze the RGB values of the fluorescence by a smartphone application. By incorporating this probe into a polyacrylonitrile (PAN) layer, we synthesized a film composite that could effectively remove FA in real samples including milk and chemical factory wastewater, and the removal rate reached 98.52% and 95.38% respectively. Moreover, the potential of the film to remove gaseous FA was confirmed by experiments as well.

An Intelligent Biomimetic Nanoplatform for Holistic Treatment of Metastatic Triple-Negative Breast Cancer via Photothermal Ablation and Immune Remodeling.

Metastasis is one of the main causes of failure in the treatment of triple-negative breast cancer (TNBC). Immunotherapy brings hope and opportunity to solve this challenge, while its clinical applications are greatly inhibited by the tumor immunosuppressive environment. Here, an intelligent biomimetic nanoplatform was designed based on dendritic large-pore mesoporous silica nanoparticles (DLMSNs) for suppressing metastatic TNBC by combining photothermal ablation and immune remodeling. Taking advantage of the ordered large-pore structure and easily chemically modified property of DLMSNs, the copper sulfide (CuS) nanoparticles with high photothermal conversion efficiency were in situ deposited inside the large pores of DLMSNs, and the immune adjuvant resiquimod (R848) was loaded controllably. A homogenous cancer cell membrane was coated on the surfaces of these DLMSNs, followed by conjugation with the anti-PD-1 peptide AUNP-12 through a polyethylene glycol linker with an acid-labile benzoic-imine bond. The thus-obtained AM@DLMSN@CuS/R848 was applied to holistically treat metastatic TNBC in vitro and in vivo. The data showed that AM@DLMSN@CuS/R848 had a high TNBC-targeting ability and induced efficient photothermal ablation on primary TNBC tumors under 980 nm laser irradiation. Tumor antigens thus generated and increasingly released R848 by response to the photothermal effect, combined with AUNP-12 detached from AM@DLMSN@CuS/R848 in the weakly acidic tumor microenvironment, synergistically exerted tumor vaccination, and T lymphocyte activation functions on immune remodeling to prevent TNBC recurrence and metastasis. Taken together, this study provides an intelligent biomimetic nanoplatform to enhance therapeutic outcomes in metastatic TNBC.

[Effect of San'ao Decoction on ovalbum induced asthmatic mice and expression of TRPV2 in lung].

To observe the efficacy of San'ao Decoction(SAD) in diffusing the lung and relieving asthma, and its intervention effect on the expression of transient receptor potential V2(TRPV2) during alleviating asthma, this study replicated an ovalbumin(OVA)-induced asthmatic mice model, and investigated the intervention effect of SAD on the airway inflammation and airway hyperresponsiveness. The regulatory mechanisms of SAD on the mRNA and protein expressions of TRPV2 in lung tissues and the levels of interleukin-4(IL-4),-10(IL-10), nerve growth factor(NGF), prostaglandin D_2(PGD_2) in bronchoalveolar lavage fluid(BALF) were discussed. Compared with the control group, the model group showed typical asthmatic phenotype, the level of eosinophils(EOS) in peripheral blood and BALF as well as the airway hyperresponsiveness were increased(P<0.01), and pathological damage in lung tissue was serious. The mRNA and protein expressions of TRPV2 in lung tissue were increased significantly, while the levels of IL-4, IL-10, NGF and PGD_2 in BALF were elevated(P<0.05,P<0.01). SAD could relieve bronchial asthma manifested as repaired lung patholo-gical changes(P<0.05), reduce the level of EOS in blood and BALF(P<0.05, P<0.01), and improve pulmonary resistance and lung compliance(P<0.05, P<0.01). SAD could also regulate the inflammatory cytokine levels of IL-4, IL-10, NGF, PGD_2 in BALF, and reduce the gene and protein expression of TRPV2 in the lung tissue(P<0.05, P<0.01). It is verified that SAD could reduce the lung inflammation, and improve lung function in asthmatic mice. The regulatory mechanism of SAD on asthma induced by OVA might be related to the regulation of TRPV2 expression and the induced decrease of Th2-related cytokines and neuropeptides, which provides the evidences for the treatment of asthma with SAD.

The neuro-immune interaction in airway inflammation through TRPA1 expression in CD4+ T cells of asthmatic mice.

Asthma is an inflammatory disorder of the airways dominated by a Th2-type pattern. Recently, an emerging interest arises whether transient receptor potential ankyrin 1 (TRPA1) plays a potential role in the adaptive immune response. In this study, the role of TRPA1 in the development and exacerbation of asthma was explored. The classic OVA-induced asthma and OVA plus PM2.5-induced exacerbated asthma model were used. The CD4+ T cells were sorted from spleen in asthmatic and exacerbated asthmatic mice. In the BALB/c mice treated with OVA, the increased phenotype of asthma was obtained, accompanied by the high expression of TRPA1 in lung tissue and levels of IL-4, IL-13, NGF, PGD2 in BAL. In contrast, genetic deletion or pharmacological inhibition of TRPA1 alleviated the phenotype of asthma. Similarly, in wild type (WT) C57BL/6 mice treated with OVA, the high expression of TRPA1 in lung tissues was obtained, and the levels of IL-4, IL-13, NGF, PGD2 in BAL remarkably increased when compared with those in the TRPA1 deleted mice. Furthermore, high expression of TRPA1 was detected in CD4+ T cells of OVA-treated WT C57BL/6 mice. Additional detection in the asthmatic mice exacerbated by OVA plus PM2.5 also showed high TRPA1 expression in lung tissue and CD4+ T cells. All evidence confirmed that TRPA1 is essential for the development and exacerbation of asthma. More importantly, the expression of TRPA1 in CD4+ T cells of different asthmatic mice suggested that it might be involved in neuro-immune interactions in airway inflammation of asthmatic mice.

Protein Kinase A Inhibitor H89 Attenuates Experimental Proliferative Vitreoretinopathy.

Purpose: This study aimed to explore the role of the protein kinase A (PKA) pathway in proliferative vitreoretinopathy (PVR) and the effect of the PKA inhibitor H89 on experimental PVR. Methods: Epiretinal membranes (ERMs) were acquired from PVR patients and analyzed by frozen-section immunofluorescence. An in vivo model was developed by intravitreal injecting rat eyes with ARPE-19 cells and platelet-rich plasma, and changes in eye structures and vision function were observed. An in vitro epithelial-mesenchymal transition (EMT) cell model was established by stimulating ARPE-19 cells with transforming growth factor (TGF)-ß. Alterations in EMT-related genes and cell function were detected. Mechanistically, PKA activation and activity were explored to assess the relationship between TGF-ß1 stimulation and the PKA pathway. The effect of H89 on the TGF-ß-Smad2/3 pathway was detected. RNA sequencing was used to analyze gene expression profile changes after H89 treatment. Results: PKA was activated in human PVR membranes. In vivo, H89 treatment protected against structural changes in the retina and prevented decreases in electroretinogram b-wave amplitudes. In vitro, H89 treatment inhibited EMT-related gene alterations and partially reversed the functions of the cells. TGF-ß-induced PKA activation was blocked by H89 pretreatment. H89 did not affect the phosphorylation or nuclear translocation of regulatory Smad2/3 but increased the expression of inhibitory Smad6. Conclusions: PKA pathway activation is involved in PVR pathogenesis, and the PKA inhibitor H89 can effectively inhibit PVR, both in vivo and in vitro. Furthermore, the protective effect of H89 is related to an increase in inhibitory Smad6.