Integrating Photoelectrochemical Feature on a Hydrovoltaic Chip with High-Salinity Adaption as a Self-Powered Device for Formaldehyde Monitoring.

Alternative energy sources are required due to the decline in fossil fuel resources. Therefore, devices that utilize hydrovoltaic technology and light energy have drawn widespread attention because they are emission-free and solar energy is inexhaustible. However, previous investigations mainly focused on accelerating the water evaporation rate at the electrode interface. Here, a cooperative photoelectrochemical effect on a hydrovoltaic chip is achieved using NH2-MIL-125-modified TiO2 nanotube arrays (NTs). This device demonstrated significantly improved evaporation-triggered electricity generation. Under LED illumination, the open-circuit voltage (VOC) of the NH2-MIL-125/TiO2NTs active layer of the hydrovoltaic chip was enhanced by 90.3% (up to 400.2 mV). Furthermore, the prepared hydrovoltaic chip showed good high-salinity tolerance, maintaining 74.6% of its performance even in 5 M NaCl. By introducing a Schiff-based reaction between the active layer and formaldehyde, a fully integrated flexible sensor was successfully fabricated for formaldehyde monitoring, and a low limit of detection of 5.2 × 10-9 M was achieved. This novel strategy for improving the performance of hydrovoltaic devices offers a completely new general approach to construct self-powered devices for point-of-care sensing.

Photodynamic-Assisted Electrochemiluminescence Enhancement toward Advanced BODIPY for Precision Diagnosis of Parkinson.

Nowadays, signal enhancement is imperative to increase sensitivity of advanced ECL devices for expediting their promising applications in clinic. In this work, photodynamic-assisted electrochemiluminescence (PDECL) device was constructed for precision diagnosis of Parkinson, where an advanced emitter was prepared by electrostatically linking 2,6-dimethyl-8-(3-carboxyphenyl)4,4'-difluoroboradiazene (BET) with 1-butyl-3-methylimidazole tetrafluoroborate ([BMIm][BF4]). Specifically, protoporphyrin IX (PPIX) can trigger the photodynamic reaction under light irradiation with a wavelength of 450 nm to generate lots of singlet oxygen (1O2), showing a 2.43-fold magnification in the ECL responses. Then, the aptamer (Apt) was assembled on the functional BET-[BMIm] for constructing a "signal off" ECL biosensor. Later on, the PPIX was embedded into the G-quadruplex (G4) of the Apt to magnify the ECL signals for bioanalysis of α-synuclein (α-syn) under light excitation. In the optimized surroundings, the resulting PDECL sensor has a broad linear range of 100.0 aM ∼ 10.0 fM and a low limit of detection (LOD) of 63 aM, coupled by differentiating Parkinson patients from normal individuals according to the receiver operating characteristic (ROC) curve analysis of actual blood samples. Such research holds great promise for synthesis of other advanced luminophores, combined with achieving an early clinical diagnosis.

Pore-Forming Toxin-Driven Recovery of Peroxidase-Mimicking Activity in Biomass Channels for Label-Free Electrochemical Bacteria Sensing.

The development of sensitive, selective, and rapid methods to detect bacteria in complex media is essential to ensuring human health. Virulence factors, particularly pore-forming toxins (PFTs) secreted by pathogenic bacteria, play a crucial role in bacterial diseases and serve as indicators of disease severity. In this study, a nanochannel-based label-free electrochemical sensing platform was developed for the detection of specific pathogenic bacteria based on their secreted PFTs. In this design, wood substrate channels were functionalized with a Fe-based metal-organic framework (FeMOF) and then protected with a layer of phosphatidylcholine (PC)-based phospholipid membrane (PM) that serves as a peroxidase mimetic and a channel gatekeeper, respectively. Using Staphylococcus aureus (S. aureus) as the model bacteria, the PC-specific PFTs secreted by S. aureus perforate the PM layer. Now exposed to the FeMOF, uncharged 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonate) (ABTS) molecules in the electrolyte undergo oxidation to cationic products (ABTS•+). The measured transmembrane ionic current indicates the presence of S. aureus and methicillin-resistant S. aureus (MRSA) with a low detection limit of 3 cfu mL-1. Besides excellent specificity, this sensing approach exhibits satisfactory performance for the detection of target bacteria in the complex media of food.

Dual amplification for PEC ultrasensitive aptasensing of biomarker HER-2 based on Z-scheme UiO-66/CdIn2S4 heterojunction and flower-like PtPdCu nanozyme.

As an important prognostic indicator in breast cancer, human epithelial growth factor receptor-2 (HER-2) is of importance for assessing prognosis of breast cancer patients, whose accurate and facile analysis are imperative in clinical diagnosis and treatment. Herein, photoactive Z-scheme UiO-66/CdIn2S4 heterojunction was constructed by a hydrothermal method, whose optical property and photoactivity were critically investigated by a range of techniques, combined by elucidating the interfacial charge transfer mechanism. Meanwhile, PtPdCu nanoflowers (NFs) were fabricated by a simple aqueous wet-chemical method, whose peroxidase (POD)-mimicking catalytic activity was scrutinized by representative tetramethylbenzidine (TMB) oxidation in H2O2 system. Taken together, the UiO-66/CdIn2S4 based photoelectrochemical (PEC) aptasensor was established for quantitative analysis of HER-2, where the detection signals were further magnified through catalytic precipitation reaction towards 4-chloro-1-naphthol (4-CN) oxidation (assisted by the PtPdCu NFs nanozyme). The PEC aptasensor presented a broader linear range within 0.1 pg mL-1-0.1 µg mL-1 and a lower limit of detection of 0.07 pg mL-1. This work developed a new PEC aptasensor for ultrasensitive determination of HER-2, holding substantial promise for clinical diagnostics.

Lead Optimization of Butyrolactone I as an Orally Bioavailable Antiallergic Agent Targeting FcγRIIB.

Food allergy (FA) poses a growing global food safety concern, yet no effective cure exists in clinics. Previously, we discovered a potent antifood allergy compound, butyrolactone I (BTL-I, 1), from the deep sea. Unfortunately, it has a very low exposure and poor pharmacokinetic (PK) profile in rats. Therefore, a series of structural optimizations toward the metabolic pathways of BTL-I were conducted to provide 18 derives (2-19). Among them, BTL-MK (19) showed superior antiallergic activity and favorable pharmacokinetics compared to BTL-I, being twice as potent with a clearance (CL) rate of only 0.5% that of BTL-I. By oral administration, Cmax and area under the concentration-time curve (AUC0-∞) were 565 and 204 times higher than those of BTL-I, respectively. These findings suggest that butyrolactone methyl ketone (BTL-BK) could serve as a drug candidate for the treatment of FAs and offer valuable insights into optimizing the druggability of lead compounds.

MOF-derived sandwich-structured dual Z-Scheme Co9S8@ZnIn2S4/CdSe hollow nanocages heterojunction: Target-induced ultrasensitive photoelectrochemical sensing of chlorpyrifos.

Exploring efficient photoactive material presents an intriguing opportunity to enhance the analytical performance of photoelectrochemical (PEC) sensor in the environmental analysis. In this work, a sandwich-structured multi-interface Co9S8@ZnIn2S4/CdSe QDs dual Z-Scheme heterojunction, derived from metal-organic framework (MOF), was synthesized as a sensing platform for chlorpyrifos detection, by integrating with enzyme-induced in situ insoluble precipitates strategy. The meticulously designed Co9S8@ZnIn2S4/CdSe QDs exhibited enhanced charge separation efficiency and was proved to be a highly effective sensing platform for the immobilization of biomolecules, attributing to the intrinsic dual Z-Scheme heterojunction and the distinctive hollow structure. The proposed PEC sensing platform combined with enzyme-induced in situ precipitate signal amplification strategy achieved superior performance for sensing of chlorpyrifos (CPF), showing in wide linear range (1.0 pg mL-1-100 ng mL-1), with a limit of detection (0.6 pg mL-1), excellent selectivity, and stability. This work offers valuable insights for the design of novel advanced photoactive materials aimed at detecting environmental pollutants with low level concentration.

Effects of Cu2O nanoparticles on the kinetic characteristics of rapid chlorophyll fluorescence induction and related genes in wheat seedlings.

Metal nanoparticles could be accumulated in soils, which threatens the ecological stability of crops. Investigating the effects of cuprous oxide nanoparticles (Cu2O-NPs) on photosystem Ⅱ (PSⅡ) of wheat seedling leaves holds considerable importance in comprehending the implications of Cu2O-NPs on crop photosynthesis. Following the hydroponic method, we investigated the effects of 0, 10, 50, 100, and 200 mg·L-1 Cu2O-NPs on chlorophyll fluorescence induction kinetics and photosynthetic-related genes in wheat seedlings of "Zhoumai 18". The results showed that, with the increases of Cu2O-NPs concentrations, chlorophyll contents in wheat leaves decreased, and the standardization of the OJIP curve showed a clearly K-phase (ΔK＞0). Cu2O-NPs stress increased the parameters of active PSⅡ reaction centers, including the absorption flux per active RC (ABS/RC), the trapping flux per active RC (TRo/RC), the electron transport flux per active RC (ETo/RC), and the dissipation flux per active RC (DIo/RC). Cu2O-NPs stress decreased the parameters of PSⅡ energy distribution ratio including the maximum quantum yield of PSⅡ (φPo), the quantum yield of electron transport from QA (φEo), and the probability that a trapped exciton moved an electron further than QA (Ψo), while increased the quantum ratio for heat dissipation (φDo). Moreover, there was a decrease in photosynthetic quantum yield Y(Ⅱ), photochemical quenching coefficient (qP), net photosynthetic rate (Pn), stomatal conductance (gs), intercellular CO2 concentration (Ci), and transpiration rate (Tr) of leaves with the increases of Cu2O-NPs concentration. Under Cu2O-NPs stress, the expression levels of genes which included PSⅡ genes (PsbD, PsbP, Lhcb1), Rubisco large subunit genes (RbcL), cytochrome b6/f complex genes (PetD, Rieske), and ATP synthase genes (AtpA, AtpB, AtpE, AtpI) were downregulated. These results indicated that Cu2O-NPs stress altered the activity and structure of PSⅡ in wheat seedlings, affected the activity of PSⅡ reaction centers, performance parameters of PSⅡ donor and acceptor sides. PSⅡ related genes were downregulated and exhibited significant concentration effects.

Zeolitic imidazole framework-derived rich-Zn-Co3O4/N-doped porous carbon with multiple enzyme-like activities for synergistic cancer therapy.

Reactive oxygen species (ROS)-centered chemodynamic therapy (CDT) holds significant potential for tumor-specific treatment. However, insufficient endogenous H2O2 and extra glutathione within tumor microenvironment (TME) severely deteriorate the CDT's effectiveness. Herein, rich-Zn-Co3O4/N-doped porous carbon (Zn-Co3O4/NC) was fabricated by two-step pyrolysis, and applied to build high-efficiency nano-platform for synergistic cancer therapy upon combination with glucose oxidase (GOx), labeled Zn-Co3O4/NC-GOx for clarity. Specifically, the multiple enzyme-like activities of the Zn-Co3O4/NC were scrutinously investigated, including peroxidase-like activity to convert H2O2 to O2∙-, catalase-like activity to decompose H2O2 into O2, and oxidase-like activity to transform O2 to O2∙-, which achieved the CDT through the catalytic cascade reaction. Simultaneously, GOx reacted with intracellular glucose to produce gluconic acid and H2O2, realizing starvation therapy. In the acidic TME, the Zn-Co3O4/NC-GOx rapidly caused intracellular Zn2+ pool overload and disrupted cellular homeostasis for ion-intervention therapy. Additionally, the Zn-Co3O4/NC exhibited glutathione peroxidase-like activity, which consumed glutathione in tumor cells and reduced the ROS consumption for ferroptosis. The tumor treatments offer some constructive insights into the nanozyme-mediated catalytic medicine, coupled by avoiding the TME limitations.

[High Resolution Emission Inventory of Greenhouse Gas and Its Characteristics in Guangdong，China].

Based on the typical city survey data and statistics of Guangdong Province， a 2018-based 3 km×3 km gridded greenhouse gas emissions inventory was developed for Guangdong Province using the combination of top-down and bottom-up emission factor methods. The inventory covered the CO2， CH4， and N2O emissions from energy， industrial processes， agriculture， land use change and forest， waste management， and indirect sources. The results showed that estimates for CO2， CH4， and N2O in Guangdong Province for the year 2018 were 8.5×108， 1.9×106， and 1.1×105 t， respectively， and 8.5×108， 4.0×107， and 3.4×107 t by equivalent carbon dioxide， totaling 9.2×108 t. CO2 was the main greenhouse gas in Guangdong Province， accounting for 92.0% of the total emissions. Energy and indirect sources were the main emission sources， accounting for 77.9% and 7.6%， respectively， totaling 85.5%. Spatial distributions illustrated that most grids were greenhouse gas emissions， whereas some others were greenhouse gas sinks； the greenhouse gas emissions were distributed mainly in the Pearl River Delta region and had certain characteristics of distribution along the road network and channels. The greenhouse gas grids of high emission were mainly the locations of high energy-consuming enterprises such as large power plants， steel mills， and cement plants.

Heterojunction of MXenes and MN4-graphene: Machine learning to accelerate the design of bifunctional oxygen electrocatalysts.

Oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) are essential for the development of excellent bifunctional electrocatalysts, which are key functions in clean energy production. The emphasis of this study lies in the rapid design and investigation of 153 MN4-graphene (Gra)/ MXene (M2NO) electrocatalysts for ORR/OER catalytic activity using machine learning (ML) and density functional theory (DFT). The DFT results indicated that CoN4-Gra/Ti2NO had both good ORR (0.37 V) and OER (0.30 V) overpotentials, while TiN4-Gra/M2NO and MN4-Gra/Cr2NO had high overpotentials. Our research further indicated orbital spin polarization and d-band centers far from the Fermi energy level, affecting the adsorption energy of oxygen-containing intermediates and thus reducing the catalytic activity. The ML results showed that the gradient boosting regression (GBR) model successfully predicted the overpotentials of the monofunctional catalysts RhN4-Gra/Ti2NO (ORR, 0.39 V) and RuN4-Gra/W2NO (OER, 0.45 V) as well as the overpotentials of the bifunctional catalyst RuN4-Gra/W2NO (ORR, 0.39 V; OER, 0.45 V). The symbolic regression (SR) algorithm was used to construct the overpotential descriptors without environmental variable features to accelerate the catalyst screening and shorten the trial-and-error costs from the source, providing a reliable theoretical basis for the experimental synthesis of MXene heterostructures.

Multifunctional Gold Nanozyme-Engineered Amphotericin B for Enhanced Antifungal Infection Therapy.

Chronic wounds of significant severity and acute injuries are highly vulnerable to fungal infections, drastically impeding the expected wound healing trajectory. The clinical use of antifungal therapeutic drug is hampered by poor solubility, high toxicity and adverse reactions, thereby necessitating the urgent development of novel antifungal therapy strategy. Herein, this study proposes a new strategy to enhance the bioactivity of small-molecule antifungal drugs based on multifunctional metal nanozyme engineering, using amphotericin B (AmB) as an example. AmB-decorated gold nanoparticles (AmB@AuNPs) are synthesized by a facile one-pot reaction strategy, and the AmB@AuNPs exhibit superior peroxidase (POD)-like enzyme activity, with maximal reaction rates (Vmax ) 3.4 times higher than that of AuNPs for the catalytic reaction of H2 O2 . Importantly, the enzyme-like activity of AuNPs significantly enhanced the antifungal properties of AmB, and the minimum inhibitory concentrations of AmB@AuNPs against Candida albicans (C. albicans) and Saccharomyces cerevisiae (S. cerevisiae) W303 are reduced by 1.6-fold and 50-fold, respectively, as compared with AmB alone. Concurrent in vivo studies conducted on fungal-infected wounds in mice underscored the fundamentally superior antifungal ability and biosafety of AmB@AuNPs. The proposed strategy of engineering antifungal drugs with nanozymes has great potential for enhanced therapy of fungal infections and related diseases.

Target-regulated photoactivities of CdS/Ni-MOF heterojunction with [Ru(bpy)2dppz]2+ intercalator: a bisphenol A photoelectrochemical aptasensor.

Bisphenol A (BPA), an important endocrine disrupting compound, has infiltrated human daily lives through electronic devices, food containers, and children's toys. Developing of novel BPA assay methods with high sensitivity holds tremendous importance in valuing the pollution state. Here, we constructed an ultrasensitive photoelectrochemical (PEC) aptasensor for BPA determination by regulating photoactivities of CdS/Ni-based metal-organic framework (CdS/Ni-MOF) with [Ru(bpy)2dppz]2+ sensitizer. CdS/Ni-MOF spheres exhibited excellent photocatalytic performance, serving as a potential sensing platform for the construction of target recognition process. [Ru(bpy)2dppz]2+ were embedded into DNA double-stranded structure, functioning as sensitizer for modulating the signal response of the developed PEC aptasensor. The proposed PEC sensor exhibited outstanding analytical performances, including a wide linear range (0.1 to 1000.0 nM), low detection limit (0.026 nM, at 3σ/m), excellent selectivity, and high stability. This work provides a perspective for the design of ideal photosensitive materials and signal amplification strategies and extends their application in environment analysis.

Diets intervene osteoporosis via gut-bone axis.

Osteoporosis is a systemic skeletal disease that seriously endangers the health of middle-aged and older adults. Recently, with the continuous deepening of research, an increasing number of studies have revealed gut microbiota as a potential target for osteoporosis, and the research concept of the gut-bone axis has gradually emerged. Additionally, the intake of dietary nutrients and the adoption of dietary patterns may affect the gut microbiota, and alterations in the gut microbiota might also influence the metabolic status of the host, thus adjusting bone metabolism. Based on the gut-bone axis, dietary intake can also participate in the modulation of bone metabolism by altering abundance, diversity, and composition of gut microbiota. Herein, combined with emerging literatures and relevant studies, this review is aimed to summarize the impacts of different dietary components and patterns on osteoporosis by acting on gut microbiota, as well as underlying mechanisms and proper dietary recommendations.

Supramolecular host-guest interaction triggered dye extraction from metal-organic framework for dual-mode ATP sensing from serum.

Adenosine triphosphate (ATP) universally exists in all living organisms and holds a paramount role as a fundamental energy molecule in daily life. The abnormal concentration of ATP is closely related to many diseases, making the highly efficient detection of ATP very urgent. In this study, a dual-mode sensing system was developed to detect ATP sensitively and selectively via both DPV and fluorescence (FL) techniques, based on the strong interaction of ATP and Zn (II) nodes of zeolitic imidazolate framework-90 (ZIF-90). The disassembly of ZIF-90 further induced the subsequent release of pre-loaded rhodamine B (RhB). Benefitting from the robust host-guest recognition of ß-cyclodextrin (ß-CD) towards RhB, an enzyme-free and highly specific DPV detection strategy was established with the linear detecting range of 10.0-1.0 × 108 pM and the limit of detection (LOD) as low as 0.13 pM. Meanwhile, the FL sensing mode based on RhB exhibits comparable sensing performance with the linearity range of 10.0-1.0 × 107 pM and the LOD of 0.29 pM. Furthermore, the enzyme-free ATP sensing system exhibit outstanding long-term storage stability. The two-mode sensing platform was successfully applied to detect the ATP in human serum samples with the yielded result highly agree with the results of commercial ELISA kits. This dual-mode sensing platform is inspiring and paves the road for developing high-performance biosensor, demonstrating enormous potential for vitro diagnosis and practice clinic.

Therapeutic effect of iturin A on Candida albicans oral infection and its pathogenic factors.

Candida albicans is responsible for conditions ranging from superficial infections such as oral or vaginal candidiasis to potentially fatal systemic infections. It produces pathogenic factors contributing to its virulence. Iturin A, a lipopeptide derived from Bacillus sp., exhibits a significant inhibitory effect against C. albicans. However, its exact mechanism in mitigating the pathogenic factors of C. albicans remains to be elucidated. This study aimed to explore the influence of iturin A on several pathogenic attributes of C. albicans, including hypha formation, cell membrane permeability, cell adhesion, biofilm formation, and therapeutic efficacy in an oral C. albicans infection model in mice. The minimal inhibitory concentration of iturin A against C. albicans was determined to be 25 µg/mL in both YEPD and RPMI-1640 media. Iturin A effectively inhibited C. albicans hyphal formation, decreased cell viability within biofilms, enhanced cell membrane permeability, and disrupted cell adhesion in vitro. Nonetheless, iturin A did not significantly affect the phospholipase activity or hydrophobicity of C. albicans. A comparative study with nystatin demonstrated the superior therapeutic efficacy of iturin A in a mouse model of oral C. albicans infection, significantly decreasing C. albicans count and inhibiting both fungal hypha formation and tongue surface adhesion. High-dose iturin A treatment (25 µg/mL) in mice had no significant effects on blood indices, tongue condition, or body weight, indicating the potential for iturin A in managing oral infections. This study confirmed the therapeutic potential of iturin A and provided valuable insights for developing effective antifungal therapies targeting C. albicans pathogenic factors.

Surface-enhanced Raman spectroscopy as a powerful method for the analysis of Chinese herbal medicines.

Chinese herbal medicines (CHMs) derived from nature have received increasing attention and become more popular. Due to their diverse production processes, complex ingredients, and different storage conditions, it is highly desirable to develop simple, rapid, efficient and trace detection methods to ensure the drug quality. Surface-enhanced Raman spectroscopy has the advantages of being time-saving, non-destructive, usable in aqueous environments, and highly compatible with various biomolecular samples, providing a promising analytical method for CHM. In this review, we outline the major advances in the application of SERS to the identification of raw materials, detection of bioactive constituents, characterization of adulterants, and detection of contaminants. This clearly shows that SERS has strong potential in the quality control of CHM, which greatly promotes the modernization of CHM.

BsR1, a broad-spectrum antibacterial peptide with potential for plant protection.

IMPORTANCE: This study addresses the critical need for new antibacterial drugs in the face of bacterial multidrug resistance resulting from antibiotic overuse. It highlights the significance of antimicrobial peptides as essential components of innate immunity in animals and plants, which have been proven effective against multidrug-resistant bacteria and are difficult to develop resistance against. This study successfully synthesizes a broad-spectrum antibacterial peptide, BsR1, with strong inhibitory activities against various Gram-positive and Gram-negative bacteria. BsR1 demonstrates favorable stability and a mode of action that damages bacterial cell membranes, leading to cell death. It also exhibits biological safety and shows potential in enhancing disease resistance in rice. This research offers a novel approach and potential medication for antibacterial drug development, presenting a valuable tool in combating pathogenic microorganisms, particularly in plants.

Correlation analysis and clinical significance of Musculoskeletal Ultrasound semi-quantitative grading with bone salt metabolism, Rheumatoid factor and Erythrocyte Sedimentation rate in patients with Rheumatoid Arthritis.

Objective: To determine the correlation and clinical significance of musculoskeletal ultrasound semi-quantitative grading with bone salt metabolism, rheumatoid factor and erythrocyte sedimentation rate (ESR) in patients with rheumatoid arthritis. Methods: This is a clinical comparative study. A total of 240 patients with rheumatoid arthritis admitted to Baoding NO.1 Central Hospital were selected according to the DAS28 score of rheumatoid arthritis, and were divided into four groups, with 60 cases in each group from May 2020 to May 2022. The differences and correlation of musculoskeletal ultrasound semi-quantitative grading, bone metabolism indicators, erythrocyte sedimentation rate and rheumatoid factor among the four groups were statistically analyzed. Results: The scores of bone erosion, synovial hyperplasia, joint effusion and intrasynovial blood flow in Group-H were significantly higher than those in Group-R, L and M, with statistically significant differences(p=0.00). The procollagen Type-1 N-terminal propeptide(P1NP), bone-specific alkaline phosphatase(BALP) and osteoprotegerin(OPG) in Group-H were significantly lower than those in Group-R, L and M, with statistically significant differences(p=0.00); The tartrate-resistant acid phosphatase(TRAC) in Group-H was significantly higher than that in Group-R, L and M, with a statistically significant difference(p=0.00). The levels of RF and ESR in Group-H were significantly higher than those in Group-R, L and M, with statistically significant differences(p=0.00). Conclusion: Musculoskeletal ultrasound semi-quantitative grading is correlated with the level of bone salt metabolism, rheumatoid factor and ESR in patients with rheumatoid arthritis. It can be combined with laboratory examination to objectively judge the severity of the course of rheumatoid arthritis.

Pro-Fibrotic Role of Interleukin-4 in Influencing Idiopathic Epiretinal Membrane in Cataract Patients: Analysis From Clinical-Experimental Approaches.

Purpose: To evaluate the role of interleukin-4 in influencing idiopathic epiretinal membrane (iERM) formation and early progression post cataract surgery (PCS) from clinical and experimental perspectives. Methods: We quantified levels of IL-4 in aqueous humor (AH) samples from 22 iERM patients and 31 control subjects collected before and 20 hours after cataract surgeries using ELISA. After a 3-month follow-up, the association between IL-4 levels and iERM progression measurements was identified. In addition, in vitro studies were conducted to investigate the effects of IL-4 on primary rat retinal Müller glia proliferation, migration, and glial-mesenchymal transition (GMT). Results: Concentrations of IL-4 were significantly higher in preoperative AH samples from iERM patients versus controls (P = 0.006). Postoperatively, although IL-4 levels were elevated in both groups compared to their respective preoperative levels, they were even more obviously so in the iERM group (P < 0.001). Multivariate linear regression analyses revealed that, postoperatively, IL-4 level elevation was positively associated with macular volume and thickness increase (both P < 0.05) in iERM patients. However, no correlations were observed between IL-4 level (changes) and clinical characters in the controls. In vitro studies demonstrated that IL-4 promoted Müller glia proliferation and migration and increased the expression of GMT-related markers in a manner independent of transforming growth factor-ß1 (TGF-ß1). Conclusions: IL-4 plays a crucial pro-fibrotic role in iERM formation and early progression 3 months PCS possibly by stimulating Müller glia proliferation, migration, and GMT in a TGF-ß1-independent manner. Translational Relevance: The current study suggests the potential of IL-4 as a novel therapeutic target for iERM.

Intrinsic cancer cell phosphoinositide 3-kinase δ regulates fibrosis and vascular development in cholangiocarcinoma.

BACKGROUND & AIMS: The class I- phosphatidylinositol-3 kinases (PI3Ks) signalling is dysregulated in almost all human cancers whereas the isoform-specific roles remain poorly investigated. We reported that the isoform δ (PI3Kδ) regulated epithelial cell polarity and plasticity and recent developments have heightened its role in hepatocellular carcinoma (HCC) and solid tumour progression. However, its role in cholangiocarcinoma (CCA) still lacks investigation. APPROACH & RESULTS: Immunohistochemical analyses of CCA samples reveal a high expression of PI3Kδ in the less differentiated CCA. The RT-qPCR and immunoblot analyses performed on CCA cells stably overexpressing PI3Kδ using lentiviral construction reveal an increase of mesenchymal and stem cell markers and the pluripotency transcription factors. CCA cells stably overexpressing PI3Kδ cultured in 3D culture display a thick layer of ECM at the basement membrane and a wide single lumen compared to control cells. Similar data are observed in vivo, in xenografted tumours established with PI3Kδ-overexpressing CCA cells in immunodeficient mice. The expression of mesenchymal and stemness genes also increases and tumour tissue displays necrosis and fibrosis, along with a prominent angiogenesis and lymphangiogenesis, as in mice liver of AAV8-based-PI3Kδ overexpression. These PI3Kδ-mediated cell morphogenesis and stroma remodelling were dependent on TGFß/Src/Notch signalling. Whole transcriptome analysis of PI3Kδ using the cancer cell line encyclopedia allows the classification of CCA cells according to cancer progression. CONCLUSIONS: Overall, our results support the critical role of PI3Kδ in the progression and aggressiveness of CCA via TGFß/src/Notch-dependent mechanisms and open new directions for the classification and treatment of CCA patients.