Fast Pure Shift NMR Spectroscopy Using Attention-Assisted Deep Neural Network.

Pure shift NMR spectroscopy enables the robust probing on molecular structure and dynamics, benefiting from great resolution enhancements. Despite extensive application landscapes in various branches of chemistry, the long experimental times induced by the additional time dimension generally hinder its further developments and practical deployments, especially for multi-dimensional pure shift NMR. Herein, this study proposes and implements the fast, reliable, and robust reconstruction for accelerated pure shift NMR spectroscopy with lightweight attention-assisted deep neural network. This deep learning protocol allows one to regain high-resolution signals and suppress undersampling artifacts, as well as furnish high-fidelity signal intensities along with the accelerated pure shift acquisition, benefitting from the introduction of the attention mechanism to highlight the spectral feature and information of interest. Extensive results of simulated and experimental NMR data demonstrate that this attention-assisted deep learning protocol enables the effective recovery of weak signals that are almost drown in the serious undersampling artifacts, and the distinction and recognition of close chemical shifts even though using merely 5.4% data, highlighting its huge potentials on fast pure shift NMR spectroscopy. As a result, this study affords a promising paradigm for the AI-assisted NMR protocols toward broader applications in chemistry, biology, materials, and life sciences, and among others.

Poly (ionic liquid) cross-linked hydrogel encapsulated with AuPt nanozymes for the smartphone-based colorimetric detection of zearalenone.

A poly (ionic liquid) enhanced poly(acrylamide-acrylic acid) (PIL-PAM/AA) hydrogel-based colorimetric sensor was designed to detect zearalenone (ZEN). Different AuxPty nanoparticles were synthesized via the on-pot method. Through the kinetic analysis and the theoretical calculation, Au0.4Pt0.6 possessed the relatively low energy barriers to adsorb and decompose H2O2 so that it exhibited relatively better catalytic activity (Km = 2.02 × 10-3, Vmax = 6.14 × 10-7). AuPt nanoparticles were encapsulated into PIL-PAM/AA hydrogel via the interaction between aptamer and cDNA. In the presence of ZEN, the embedded AuPt nanoparticles were released to complete the catalytic reaction. Coupled with the smartphone application, the established method provided the linear range of 1-250 ng mL-1, with a detection limit of 0.6979 ng mL-1 for ZEN. Meanwhile, it also possessed excellent selectivity and good anti-interference performance. In wheat and corn samples, spiked recoveries were ranging from 75% to 113.30%.

Design, synthesis and biological evaluation of indoline-maleimide conjugates as potential antitumor agents for the treatment of colorectal cancer.

An efficient protocol for direct coupling of maleimides and indolines at the C7-position was achieved under Rh(III) catalysis. Thirty four novel indoline-maleimide conjugates were prepared in good to excellent yields using this method. All compounds were evaluated for their anti-proliferative effect against colorectal cell lines. Among them, compound 3ab showed the most potent anti-proliferative activity against the CRC cells, and displayed low toxicity in the normal cell. Further investigation indicated that 3ab could effectively suppress the proliferation and migration of CRC cells, along with inducing cell cycle arrest and apoptosis. Mechanistic studies revealed that compound 3ab inhibited the proliferation of CRC cells via suppressing the AKT/GSK-3ß pathway. In vivo evaluation demonstrated remarkable antitumor effect of 3ab (10 mg/kg) in the HCT116 xenograft model with no obvious toxicity, which is superior to that of 5-Fluorouracil (20 mg/kg). Therefore, conjugate 3ab could be considered as a potential CRC therapy agent for further development.

A20 Promoter rs5029924 Concomitant with rs2230926 and rs5029937 May Be a Prognostic Predictor for Joint Deformity or Refractory Rheumatoid Arthritis.

Background: There have been several studies regarding the susceptibility of A20 gene SNPs (rs2230926 and rs5029937) in rheumatoid arthritis (RA). However, little is known about the association between polymorphisms in the A20 promoter and RA. The aim of this study was to investigate the characteristics of A20 promoter polymorphisms and the association between these polymorphisms and clinical significance in Chinese RA patients. Methods: PCR and sequencing were used to identify A20 gene polymorphisms in peripheral blood mononuclear cells (PBMCs) from 123 RA cases and 31 healthy individuals. Results: Only one SNP (rs5029924) in the A20 gene promoter was identified in RA patients and healthy individuals. 6 patients who carried heterozygous rs5029924 (3918C>T) together with heterozygous rs5029937 (11,571 G>T) and rs2230926 (12,486 T>G, Phe127Cys) suffered from joints deformity or refractory RA. Conclusion: We reported the A20 promoter polymorphism rs5029924 in RA patients for the first time. rs5029924 concomitant with rs2230926 and rs5029937 may be a prognostic predictor for joint deformity or refractory RA.

Reduced graphene oxide-wrapped ZnS-SnS2 heterojunction bimetallic hollow cubic boxes as high-magnification and long lifespan supercapacitor anode materials.

Metal sulfides have attracted extensive attention due to their excellent electrochemical performance. However, issues such as poor conductivity and severe volume expansion during charge and discharge processes affect the applications of sulfides as electrode materials. Here, a combination of coprecipitation and high-temperature sulfidation methods are employed to synthesize a ZnS-SnS2 composite with a hollow cubic structure, which is further composited with reduced graphene oxide (RGO) to form ZnS-SnS2 hollow cubic boxes encapsulated in a conductive framework of reduced graphene oxide (RGO) (denoted as ZnS-SnS2@RGO) for electrode materials. The hollow structure effectively alleviates the pulverization of ZnS-SnS2@RGO caused by volume expansion during charge and discharge processes. The heterogeneous structure formed by ZnS and SnS2 effectively reduces the electron transfer resistance of the material. The use of RGO wrapping enhances the conductivity of the ZnS-SnS2 hollow cubic boxes, and RGO's dispersion effect on the ZnS-SnS2 cubes improves particle agglomeration, further mitigating volume expansion of the material. These results indicate the outstanding electrochemical performance of heterostructural ZnS-SnS2 hollow cubic electrodes encapsulated with reduced graphene oxide as a conductive framework. The fabrication process provides a novel approach for addressing volume expansion and poor conductivity issues in other pseudocapacitive materials.

Precise Modulation of Pericyte Dysfunction by a Multifunctional Nanoprodrug to Ameliorate Alzheimer's Disease.

Pericyte dysfunction severely undermines cerebrovascular integrity and exacerbates neurodegeneration in Alzheimer's disease (AD). However, pericyte-targeted therapy is a yet-untapped frontier for AD. Inspired by the elevation of vascular cell adhesion molecule-1 (VCAM-1) and reactive oxygen species (ROS) levels in pericyte lesions, we fabricated a multifunctional nanoprodrug by conjugating the hybrid peptide VLC, a fusion of the VCAM-1 high-affinity peptide VHS and the neuroprotective apolipoprotein mimetic peptide COG1410, to curcumin (Cur) through phenylboronic ester bond (VLC@Cur-NPs) to alleviate complex pericyte-related pathological changes. Importantly, VLC@Cur-NPs effectively homed to pericyte lesions via VLC and released their contents upon ROS stimulation to maximize their regulatory effects. Consequently, VLC@Cur-NPs markedly increased pericyte regeneration to form a positive feedback loop and thus improved neurovascular function and ultimately alleviated memory defects in APP/PS1 transgenic mice. We present a promising therapeutic strategy for AD that can precisely modulate pericytes and has the potential to treat other cerebrovascular diseases.

Genome-Wide Investigation of Class III Peroxidase Genes in Brassica napus Reveals Their Responsiveness to Abiotic Stresses.

Brassica napus (B. napus) is susceptible to multiple abiotic stresses that can affect plant growth and development, ultimately reducing crop yields. In the past, many genes that provide tolerance to abiotic stresses have been identified and characterized. Peroxidase (POD) proteins, members of the oxidoreductase enzyme family, play a critical role in protecting plants against abiotic stresses. This study demonstrated a comprehensive investigation of the POD gene family in B. napus. As a result, a total of 109 POD genes were identified across the 19 chromosomes and classified into five distinct subgroups. Further, 44 duplicate events were identified; of these, two gene pairs were tandem and 42 were segmental. Synteny analysis revealed that segmental duplication was more prominent than tandem duplication among POD genes. Expression pattern analysis based on the RNA-seq data of B. napus indicated that BnPOD genes were expressed differently in various tissues; most of them were expressed in roots rather than in other tissues. To validate these findings, we performed RT-qPCR analysis on ten genes; these genes showed various expression levels under abiotic stresses. Our findings not only furnish valuable insights into the evolutionary dynamics of the BnPOD gene family but also serve as a foundation for subsequent investigations into the functional roles of POD genes in B. napus.

Effect of early cannulation with metal needles on arteriovenous fistula patency in patients undergoing hemodialysis.

BACKGROUND: Autogenous arteriovenous fistula (AVF) is the preferred vascular access mode. However, the earliest possible time for AVF puncture and whether premature puncture affects the AVF patency rate remain unclear. METHODS: In this multicenter retrospective cohort study, adult uremic patients who underwent AVF surgery for the first time at Taizhou Hospital or Enze Hospital of Zhejiang Province between September 1, 2018 and August 31, 2021 were enrolled. All patients were followed up for 1 year after puncture, and the status of fistula establishment and puncture, subsequent patency, loss to follow-up, renal transplantation, conversion to peritoneal dialysis, abandonment of the fistula, and death, were recorded. RESULTS: A total of 465 patients with AVFs were included in this study, including 59 (12.7%) patients with fistulas that were cannulated within 30 days. In the early puncture group, the levels of serum creatinine and urea nitrogen were higher, while the levels of hemoglobin and albumin were lower, suggesting that these patients needed urgent dialysis. Furthermore, the rate of non-cuffed catheter use was higher, while the rate of cuffed catheter use was lower, and femoral vein puncture was preferred over internal jugular vein puncture. The mean duration of catheter indwelling was shorter in the early puncture group (19 vs 70 days, p < 0.001). The estimated AVF primary and cumulative functional patency at 12 months was 81.1% versus 82.3% and 98.3% versus 98.7% in the early puncture and control groups, respectively. Kaplan-Meier analysis revealed no significant difference in AVF primary and cumulative functional patency between the two groups. CONCLUSIONS: In patients with an established fistula in urgent need of hemodialysis, to avoid new catheterization, a puncture can be performed within 30 days in those with well-developed blood vessels after adequate ultrasound and clinical evaluation without affecting the patency of the fistula.

Recent advances in swine wastewater treatment technologies for resource recovery: A comprehensive review.

Swine wastewater (SW), characterized by highly complex organic and nutrient substances, poses serious impacts on aquatic environment and public health. Furthermore, SW harbors valuable resources that possess substantial economic potential. As such, SW treatment technologies place increased emphasis on resource recycling, while progressively advancing towards energy saving, sustainability, and circular economy principles. This review comprehensively encapsulates the state-of-the-art knowledge for treating SW, including conventional (i.e., constructed wetlands, air stripping and aerobic system) and resource-utilization-based (i.e., anaerobic digestion, membrane separation, anaerobic ammonium oxidation, microbial fuel cells, and microalgal-based system) technologies. Furthermore, this research also elaborates the key factors influencing the SW treatment performance, such as pH, temperature, dissolved oxygen, hydraulic retention time and organic loading rate. The potentials for reutilizing energy, biomass and digestate produced during the SW treatment processes are also summarized. Moreover, the obstacles associated with full-scale implementation, long-term treatment, energy-efficient design, and nutrient recovery of various resource-utilization-based SW treatment technologies are emphasized. In addition, future research prospective, such as prioritization of process optimization, in-depth exploration of microbial mechanisms, enhancement of energy conversion efficiency, and integration of diverse technologies, are highlighted to expand engineering applications and establish a sustainable SW treatment system.

Multidimensional autophagy nano-regulator boosts Alzheimer's disease treatment by improving both extra/intraneuronal homeostasis.

Intraneuronal dysproteostasis and extraneuronal microenvironmental abnormalities in Alzheimer's disease (AD) collectively culminate in neuronal deterioration. In the context of AD, autophagy dysfunction, a multi-link obstacle involving autophagy downregulation and lysosome defects in neurons/microglia is highly implicated in intra/extraneuronal pathological processes. Therefore, multidimensional autophagy regulation strategies co-manipulating "autophagy induction" and "lysosome degradation" in dual targets (neuron and microglia) are more reliable for AD treatment. Accordingly, we designed an RP-1 peptide-modified reactive oxygen species (ROS)-responsive micelles (RT-NM) loading rapamycin or gypenoside XVII. Guided by RP-1 peptide, the ligand of receptor for advanced glycation end products (RAGE), RT-NM efficiently targeted neurons and microglia in AD-affected region. This nano-combination therapy activated the whole autophagy-lysosome pathway by autophagy induction (rapamycin) and lysosome improvement (gypenoside XVII), thus enhancing autophagic degradation of neurotoxic aggregates and inflammasomes, and promoting Aß phagocytosis. Resultantly, it decreased aberrant protein burden, alleviated neuroinflammation, and eventually ameliorated memory defects in 3 × Tg-AD transgenic mice. Our research developed a multidimensional autophagy nano-regulator to boost the efficacy of autophagy-centered AD therapy.

The impact of green-listed companies on rural ecological environments in China: A spatial heterogeneity and empirical analysis.

Based on the panel data of 22 inland provinces in China from 2010 to 2020, this study constructs and measures the level of rural ecological environment in China. The impact of the financial performance of green-listed companies on the rural ecological environment and its moderating and threshold effects are analyzed. The following conclusions are drawn: (1) During 2010-2020, China's rural ecological environment shows a trend of "fluctuating-decreasing-rising" with significant regional non-equilibrium characteristics. (2) The financial performance of green-listed companies has a significantly negative impact on rural ecology. This negative impact has a crucial heterogeneous feature, with a more significant negative impact in areas with a higher rural ecological environment index and less substantial performance in regions with a lower rural ecological environment index. (3) There is a significant positive moderating effect of education level and digitalization on the relationship between the financial performance of green-listed companies on the level of rural ecological development. As moderating variables, the digitalization and education level weakens the negative impact of green-listed companies' performance on the ecological environment. The positive impact of the financial performance of green-listed companies on the development level of the rural ecological environment is more vital in areas with higher per capita education levels and digitalization in rural areas. (4) There is a significant threshold effect on the financial performance of green-listed companies on the level of rural ecological development. When the financial performance of green-listed companies exceeds a particular threshold value, the impact of the financial performance of green-listed companies on the development level of the rural ecological environment is significantly positive. Based on the above findings, this paper puts forward corresponding countermeasure suggestions.

Design, synthesis, in vitro and in vivo biological evaluation of pterostilbene derivatives for anti-inflammation therapy.

Pterostilbene (PST) is a naturally derived stilbene compound in grapes, blueberries, and other fruits. It is also a natural dietary compound with a wide range of biological activities such as antioxidant, anti-inflammatory, antitumor, and so on. Structural modifications based on the chemical scaffold of the pterostilbene skeleton are of great importance for drug discovery. In this study, pterostilbene skeletons were used to design novel anti-inflammatory compounds with high activity and low toxicity. A total of 30 new were found and synthesised, and their anti-inflammatory activity and safety were screened. Among them, compound E2 was the most active (against NO: IC50 = 0.7 µM) than celecoxib. Further studies showed that compound E2 exerted anti-inflammatory activity by blocking LPS-induced NF-κB/MAPK signalling pathway activation. In vivo experiments revealed that compound E2 had a good alleviating effect on acute colitis in mice. In conclusion, compound E2 may be a promising anti-inflammatory lead compound.

Platinum-Loaded Cerium Oxide Capable of Repairing Neuronal Homeostasis for Cerebral Ischemia-Reperfusion Injury Therapy.

Effective neuroprotective agents are required to prevent neurological damage caused by reactive oxygen species (ROS) generated by cerebral ischemia-reperfusion injury (CIRI) following an acute ischemic stroke. Herein, it is aimed to develop the neuroprotective agents of cerium oxide loaded with platinum clusters engineered modifications (Ptn-CeO2). The density functional theory calculations show that Ptn-CeO2 could effectively scavenge ROS, including hydroxyl radicals (·OH) and superoxide anions (·O2 -). In addition, Ptn-CeO2 exhibits the superoxide dismutase- and catalase-like enzyme activities, which is capable of scavenging hydrogen peroxide (H2O2). The in vitro studies show that Ptn-CeO2 could adjust the restoration of the mitochondrial metabolism to ROS homeostasis, rebalance cytokines, and feature high biocompatibility. The studies in mice CIRI demonstrate that Ptn-CeO2 could also restore cytokine levels, reduce cysteine aspartate-specific protease (cleaved Caspase 3) levels, and induce the polarization of microglia to M2-type macrophages, thus inhibiting the inflammatory responses. As a result, Ptn-CeO2 inhibits the reperfusion-induced neuronal apoptosis, relieves the infarct volume, reduces the neurological severity score, and improves cognitive function. Overall, these findings suggest that the prominent neuroprotective effect of the engineered Ptn-CeO2 has a significant neuroprotective effect and provides a potential therapeutic alternative for CIRI.

A Binocular Stereo-Imaging-Perception System with a Wide Field-of-View and Infrared- and Visible Light-Dual-Band Fusion.

With the continuous evolution of autonomous driving and unmanned driving systems, traditional limitations such as a limited field-of-view, poor ranging accuracy, and real-time display are becoming inadequate to satisfy the requirements of binocular stereo-perception systems. Firstly, we designed a binocular stereo-imaging-perception system with a wide-field-of-view and infrared- and visible light-dual-band fusion. Secondly we proposed a binocular stereo-perception optical imaging system with a wide field-of-view of 120.3°, which solves the small field-of-view of current binocular stereo-perception systems. Thirdly, For image aberration caused by the wide-field-of-view system design, we propose an ellipsoidal-image-aberration algorithm with a low consumption of memory resources and no loss of field-of-view. This algorithm simultaneously solves visible light and infrared images with an aberration rate of 45% and 47%, respectively. Fourthly, a multi-scale infrared- and visible light-image-fusion algorithm is used, which improves the situational-awareness capabilities of a binocular stereo-sensing system in a scene and enhances image details to improve ranging accuracy. Furthermore, this paper is based on the Taylor model-calibration binocular stereo-sensing system of internal and external parameters for limit correction; the implemented algorithms are integrated into an NVIDIA Jetson TX2 + FPGA hardware framework, enabling near-distance ranging experiments. The fusion-ranging accuracy within 20 m achieved an error of 0.02 m, outperforming both visible light- and infrared-ranging methods. It generates the fusion-ranging-image output with a minimal delay of only 22.31 ms at a frame rate of 50 Hz.

Allergy Test Dosage of Fluorescein Detects Diabetic Retinopathy Changes in Fundus Fluorescein Angiography.

BACKGROUND: The aims of this study were to evaluate the feasibility of allergy test dosage of fluorescein sodium (1%) for Diabetic Retinopathy (DR) detection in Fundus Fluorescein Angiography (FFA) examination as compared to the regular dosage (20%). METHODS: Totally 77 eyes from 42 DR patients were included in this prospective study. Capillary non-perfusion area, neovascularization, diabetic macular edema and microaneurysms were measured by FFA and compared at 1, 5 and 15 min after intravenous injection of 1% or 20% fluorescein sodium. RESULTS: There was no statistically significant difference in the proportions of capillary non-perfusion area and diabetic macular edema as well as the amount of neovascularization between the 1% and 20% fluorescein sodium groups. Yet, the 1% group had a significantly a smaller number of microaneurysms than the 20% group at 1 min (p < 0.001) and a smaller number of eyes with diabetic macular edema than the 20% group at 5 (p = 0.032) and 15 min (p = 0.015). The images from patients with clear vitreous had better quality than the images from patients with vitreous opacity (all p < 0.05, except comparison on neovascularization at 5 min: p > 0.999). All examined indexes showed high correlations between the 1% and 20% groups (r > 0.8, p < 0.001). CONCLUSIONS: This study demonstrated that 1% fluorescein sodium could detect the changes of DR comparably to the regular dosage.

Comparing endoscopic ultrasonography and double contrast-enhanced ultrasonography in the preoperative diagnosis of gastric stromal tumor.

BACKGROUND: This study was designed to perform a comparative analysis between endoscopic ultrasonography (EUS) and double contrast-enhanced ultrasonography (DCEUS) for the preoperative diagnosis of gastric stromal tumors (GSTs). METHODS: A retrospective study was conducted involving 139 patients with histologically confirmed GSTs. All patients preoperatively underwent DCEUS and EUS. The pathology reports were treated as the baseline and were retrospectively compared with the findings of EUS and DCEUS. RESULTS: Of the 139 lesions, 120 and 113 were correctly identified by DCEUS and EUS, respectively, with an accuracy of 86.3% and 81.3%. The results revealed an insignificant difference between these two methods (p = 0.189). CONCLUSIONS: DCEUS can display not only the locations, sizes, shapes, borders, internal echoes, but also show the blood perfusion patterns of GSTs. It is a highly accurate, noninvasive, and convenient method to be used at the pre-treatment stage.

Diagnostic roles of neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, platelet-to-lymphocyte ratio, C-reactive protein, and cancer antigen 125 for ovarian cancer.

OBJECTIVE: To compare the diagnostic value of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), C-reactive protein (CRP) level, and cancer antigen 125 (CA125) level for ovarian cancer (OC). METHODS: Data of 72 patients with OC, 50 patients with benign ovarian disease, and 46 healthy controls were retrospectively analyzed, and receiver operating characteristic analysis was performed. RESULTS: The platelet count was higher in patients with a tumor diameter of ≥10 vs. <10 cm. The absolute lymphocyte count was significantly higher in patients with stage I/II OC than in those with multiple and stage III/IV OC. The absolute monocyte count, NLR, MLR, and CA125 were significantly higher in patients with multiple and stage III/IV OC than in those with single and stage I/II OC. The NLR, PLR, MLR, fibrinogen, D-dimer, CRP, and CA125 were useful for distinguishing between the OC and healthy control groups. CONCLUSIONS: Our analysis showed that the following combinations have practical diagnostic value in OC: NLR + PLR + MLR + CA125, NLR + PLR + MLR + CA125 + CRP, NLR + MLR +PLR + CA125 + CRP + fibrinogen, and NLR + MLR + PLR + CA125 + CRP + fibrinogen + D-dimer.

Effects of GLP1RAs on pregnancy rate and menstrual cyclicity in women with polycystic ovary syndrome: a meta-analysis and systematic review.

PURPOSE: This study was aimed to assess the effectiveness of Glucagon-like peptide 1 receptor agonists on pregnancy rate, menses, anthropometric and hormonal parameters in PCOS patients. METHODS: We conducted searches of the published literature in PubMed, EMBASE, Cochrane Library, Web of Science up to September 2022. Data from randomized controlled trials were obtained to assess the effects of GLP1RAs in PCOS women. Weighted mean difference, standardized mean difference, and risks ratio were employed for effect size estimation using a random-effects model. RESULTS: A total of 840 patients with 469 individuals in GLP1RAs group and 371 individuals in control group from 11 RCTs were included. GLP1RAs usage was associated with an improvement in natural pregnancy rate (RR: 1.72, 95% CI 1.22 to 2.43, P = 0.002, I2 = 0%) and menstrual regularity (SMD: 1.72, 95% CI 0.60 to 2.85, P < 0.001, I2 = 95.6%). There were no statistically significant differences in total pregnancy rate, IVF pregnancy rate between two groups, but total PR elevated in a short time after GLP1RAs as shown in subgroup analysis. Randomization to GLP1RAs treatment was associated with great improvement in HOMA-IR, BMI, WC, SHBG and a slight reduction in TT compared to control group. A decrease in TBF was seen in European population. GLP1RAs monotherapy was not superior to metformin when it came to fT, DHEAS, FAI. CONCLUSIONS: Prescription of GLP1RAs improves natural pregnancy rate, menstrual cyclicity and insulin sensitivity, anthropometrics, hormonal indexes in PCOS women.

Metal-Free Oxidative Dearomatization-Alkoxylation/Acyloxylation of Indoles: Synthesis of 2-Monosubstituted Indolin-3-ones.

A metal-free route for the preparation of 2-monosubstituted indolin-3-ones, including 2-alkoxyindolin-3-ones and 2-acyloxyindolin-3-ones from commercially available indoles, has been developed employing (bis(trifluoroacetoxy)iodo)benzene (PIFA) as an oxidant. The present protocol features mild reaction conditions, good tolerance with diverse functional groups, and a wide substrate scope, affording the desired products in good yields. This transformation is easy to scale up, and the desired products can be further modified. Most importantly, this method is suitable for the late-stage modification of bioactive molecules. Mechanism studies show that this transformation involves metal-free radical dearomatization and oxygenation. Furthermore, this method also provides a practical and efficient way to prepare indolin-3-ones from commercially available reagents in one step.

Human Placental Mesenchymal Stem Cells Relieve Primary Sclerosing Cholangitis via Upregulation of TGR5 in Mdr2-/- Mice and Human Intrahepatic Cholangiocyte Organoid Models.

Primary sclerosing cholangitis (PSC) is a biliary disease accompanied by chronic inflammation of the liver and biliary stricture. Mesenchymal stem cells (MSCs) are used to treat liver diseases because of their immune regulation and regeneration-promoting functions. This study was performed to explore the therapeutic potential of human placental MSCs (hP-MSCs) in PSC through the Takeda G protein-coupled receptor 5 (TGR5) receptor pathway. Liver tissues were collected from patients with PSC and healthy donors (n = 4) for RNA sequencing and intrahepatic cholangiocyte organoid construction. hP-MSCs were injected via the tail vein into Mdr2-/-, bile duct ligation (BDL), and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) mouse models or co-cultured with organoids to confirm their therapeutic effect on biliary cholangitis. Changes in bile acid metabolic profile were analyzed by liquid chromatography/tandem mass spectrometry (LC-MS/MS). Compared with healthy controls, liver tissues and intrahepatic cholangiocyte organoids from PSC patients were characterized by inflammation and cholestasis, and marked downregulation of bile acid receptor TGR5 expression. hP-MSC treatment apparently reduced the inflammation, cholestasis, and fibrosis in Mdr2-/-, BDL, and DDC model mice. By activating the phosphatidylinositol 3 kinase/extracellular signal-regulated protein kinase pathway, hP-MSC treatment promoted the proliferation of cholangiocytes, and affected the transcription of downstream nuclear factor κB through regulation of the binding of TGR5 and Pellino3, thereby affecting the cholangiocyte inflammatory phenotype.