Antioxidant and anti-inflammatory function of Eupatorium adenophora Spreng leaves (EASL) on human intestinal Caco-2 cells treated with tert-butyl hydroperoxide.

Chronic non-communicable diseases (CNCDs) pose a significant public health challenge. Addressing this issue, there has been a notable breakthrough in the prevention and mitigation of NCDs through the use of antioxidants and anti-inflammatory agents. In this study, we aim to explore the effectiveness of Eupatorium adenophora Spreng leaves (EASL) as an antioxidant and anti-inflammatory agent, and its potential applications. To construct a cellular model of oxidative damage and inflammation, Caco-2 cells were treated with tert-butyl hydroperoxide (t-BHP). The biocompatibility of EASL-AE with Caco-2 cells was assessed using the MTT assay, while compatibility was further verified by measuring LDH release and the protective effect against oxidative damage was also assessed using the MTT assay. Additionally, we measured intracellular oxidative stress indicators such as ROS and 8-OHdG, as well as inflammatory pathway signalling protein NFκB and inflammatory factors TNF-α and IL-1ß using ELISA, to evaluate the antioxidant and anti-inflammatory capacity of EASL-AE. The scavenging capacity of EASL-AE against free radicals was determined through the DPPH Assay and ABTS Assay. Furthermore, we measured the total phenolic, total flavonoid, and total polysaccharide contents using common chemical methods. The chemical composition of EASL-AE was analyzed using the LC-MS/MS technique. Our findings demonstrate that EASL-AE is biocompatible with Caco-2 cells and non-toxic at experimental levels. Moreover, EASL-AE exhibits a significant protective effect on Caco-2 cells subjected to oxidative damage. The antioxidant effect of EASL-AE involves the scavenging of intracellular ROS, while its anti-inflammatory effect is achieved by down-regulation of the NFκB pathway. Which in turn reduces the release of inflammatory factors TNF-α and IL-1ß. Through LC-MS/MS analysis, we identified 222 compounds in EASL-AE, among which gentianic acid, procaine and L-tyrosine were the compounds with high antioxidant capacity and may be the effective constituent for EASL-AE with antioxidant activity. These results suggest that EASL-AE is a natural and high-quality antioxidant and anti-inflammatory biomaterial that warrants further investigation. It holds great potential for applications in healthcare and other related fields.

Unravelling the health and economic burden of interstitial lung diseases in adults in Australia.

BACKGROUND: Interstitial lung diseases (ILD) are a heterogenous group of over 200 disorders affecting the pulmonary interstitium. Although there have been advances in knowledge on ILDs in Australia, the characterisation of the health and economic burden of disease remained largely undetermined until recently. OBJECTIVE: The main objective of this review is to provide a synopsis of health and economic burden of ILDs in Australia, based on recently completed research. DISCUSSION: Recent research has demonstrated that idiopathic pulmonary fibrosis (IPF) is the most frequent ILD in Australia. Incidence and prevalence of IPF have demonstrated an increasing trend over the past decades. Mortality has also increased over the past decades, but has shown a slight decreasing trend recently, since the introduction of antifibrotic medication. Health-related quality of life is poor in patients with IPF, and care is estimated to cost approximately AU$299 million per year in Australia. Early diagnosis and referral to tertiary care is crucial for favourable outcomes, and general practitioners are considerably important to this as the first interface to identify patients at risk and detect early symptoms of ILDs.

(±)-hypermonanones A-G, seven pairs of monoterpenoid polyprenylated acylphloroglucinol enantiomers from Hypericum monanthemum.

Seven pairs of undescribed monoterpenoid polyprenylated acylphloroglucinol enantiomers [(±)-hypermonanones A-G (1-7)], together with three known analogues, were identified from the whole plant of Hypericum monanthemum Hook. The structures of these compounds were determined by analyses of their UV, HRESIMS, 1D/2D NMR spectroscopic data, and NMR calculations. The absolute configurations of these compounds were assigned by ECD calculations after chiral HPLC separation. Diverse monoterpene moieties were fused at C-3/C-4 of the dearomatized acylphloroglucinol core, which led to 3,4-dihydro-2H-pyran-integrated angular or linear type 6/6/6 tricyclic skeletons in 1-7. Compounds (-)-2 and (+)-2 exhibited significant NO inhibitory activity against LPS induced RAW264.7 cells with the IC50 values of 7.07 ± 1.02 µM and 11.39 ± 0.24 µM, respectively.

Reversible Snapping of Constrained Anisotropic Hydrogels Upon Light Stimulations.

Creatures, such as Venus flytrap and hummingbirds, capable of rapid predation through snap-through transition, provide paradigms for the design of soft actuators and robots with fast actions. However, these artificial "snappers" usually need contact stimulations to trigger the flipping. Reported here is a constrained anisotropic poly(N-isopropylacrylamide) hydrogel showing fast snapping upon light stimulation. This hydrogel is prepared by flow-induced orientation of nanosheets (NSs) within a rectangular tube. The precursor containing gold nanoparticles is immediately exposed to UV light for photopolymerization to fix the ordered structure of NSs. Two ends of the slender gel are clamped to form a buckle with bistability nature, which snaps to the other side upon laser irradiation. Systematic experiments are conducted to investigate the influences of power intensity and irradiation angle of the laser, as well as thickness and buckle height of the gel, on the snapping behaviors. The fast snapping is further used to kick a plastic bead and control the switch state. Furthermore, synergetic or oscillated snapping of the gel with two buckles of opposite directions is realized by inclined irradiation of a laser or horizontal irradiation with two lasers, respectively. Such light-steered snapping of hydrogels should merit designing soft robots, energy harvests, etc.

Innovative synthesis of drug-like molecules using tetrazole as core building blocks.

Tetrazole is widely utilized as a bioisostere for carboxylic acid in the field of medicinal chemistry and drug development, enhancing the drug-like characteristics of various molecules. Typically, tetrazoles are introduced from their nitrile precursors through late-stage functionalization. In this work, we propose a novel strategy involving the use of diversely protected, unprecedented tetrazole aldehydes as building blocks. This approach facilitates the incorporation of the tetrazole group into multicomponent reactions or other chemistries, aiding in the creation of a variety of complex, drug-like molecules. These innovative tetrazole building blocks are efficiently and directly synthesized using a Passerini three-component reaction (PT-3CR), employing cost-effective and readily available materials. We further showcase the versatility of these new tetrazole building blocks by integrating the tetrazole moiety into various multicomponent reactions (MCRs), which are already significantly employed in drug discovery. This technique represents a unique and complementary method to existing tetrazole synthesis processes. It aims to meet the growing demand for tetrazole-based compound libraries and novel scaffolds, which are challenging to synthesize through other methods.

An adeno-associated virus variant enabling efficient ocular-directed gene delivery across species.

Recombinant adeno-associated viruses (rAAVs) have emerged as promising gene therapy vectors due to their proven efficacy and safety in clinical applications. In non-human primates (NHPs), rAAVs are administered via suprachoroidal injection at a higher dose. However, high doses of rAAVs tend to increase additional safety risks. Here, we present a novel AAV capsid (AAVv128), which exhibits significantly enhanced transduction efficiency for photoreceptors and retinal pigment epithelial (RPE) cells, along with a broader distribution across the layers of retinal tissues in different animal models (mice, rabbits, and NHPs) following intraocular injection. Notably, the suprachoroidal delivery of AAVv128-anti-VEGF vector completely suppresses the Grade IV lesions in a laser-induced choroidal neovascularization (CNV) NHP model for neovascular age-related macular degeneration (nAMD). Furthermore, cryo-EM analysis at 2.1 Å resolution reveals that the critical residues of AAVv128 exhibit a more robust advantage in AAV binding, the nuclear uptake and endosome escaping. Collectively, our findings highlight the potential of AAVv128 as a next generation ocular gene therapy vector, particularly using the suprachoroidal delivery route.

Engineering Tough Supramolecular Hydrogels with Structured Micropillars for Tunable Wetting and Adhesion Properties.

Soft-lithography is widely used to fabricate microstructured surfaces on plastics and elastomers for designable physical properties such as wetting and adhesions. However, it remains a big challenge to construct high-aspect-ratio microstructures on the surface of hydrogels due to the difficulty in demolding from the gel with low strength and stiffness. Demonstrated here is the engineering of tough hydrogels by soft-lithography to form well-defined micropillars. The mechanical properties of poly(acrylamide-co-methacrylic acid) hydrogels with dense hydrogen-bond associations severely depend on temperature, with Young's modulus increasing from 8.1 MPa at 15 °C to 821.8 MPa at -30 °C, enabling easy demolding at low temperatures. Arrays of micropillars are maintained on the surface of the gel, and can be used at room temperature when the gel restores soft and stretchable. The hydrogel also exhibits good shape-memory property, favoring tailoring the morphology with a switchable tilt angle of micropillars. Consequently, the hydrogel shows tunable wetting and adhesion properties, as manifested by varying contact angles and adhesion strengths. These surface properties can also be tuned by geometry and arrangement of micropillars. This facile strategy by harnessing tunable viscoelasticity of supramolecular hydrogels should be applicable to other soft materials, and broaden their applications in biomedical and engineering fields.

Development of an Interpretable Deep Learning Model for Pathological Tumor Response Assessment After Neoadjuvant Therapy.

BACKGROUND: Neoadjuvant therapy followed by surgery has become the standard of care for locally advanced esophageal squamous cell carcinoma (ESCC) and accurate pathological response assessment is critical to assess the therapeutic efficacy. However, it can be laborious and inconsistency between different observers may occur. Hence, we aim to develop an interpretable deep-learning model for efficient pathological response assessment following neoadjuvant therapy in ESCC. METHODS: This retrospective study analyzed 337 ESCC resection specimens from 2020-2021 at the Pudong-Branch (Cohort 1) and 114 from 2021-2022 at the Puxi-Branch (External Cohort 2) of Fudan University Shanghai Cancer Center. Whole slide images (WSIs) from these two cohorts were generated using different scanning machines to test the ability of the model in handling color variations. Four pathologists independently assessed the pathological response. The senior pathologists annotated tumor beds and residual tumor percentages on WSIs to determine consensus labels. Furthermore, 1850 image patches were randomly extracted from Cohort 1 WSIs and binarily classified for tumor viability. A deep-learning model employing knowledge distillation was developed to automatically classify positive patches for each WSI and estimate the viable residual tumor percentages. Spatial heatmaps were output for model explanations and visualizations. RESULTS: The approach achieved high concordance with pathologist consensus, with an R^2 of 0.8437, a RAcc_0.1 of 0.7586, a RAcc_0.3 of 0.9885, which were comparable to two senior pathologists (R^2 of 0.9202/0.9619, RAcc_0.1 of 8506/0.9425, RAcc_0.3 of 1.000/1.000) and surpassing two junior pathologists (R^2 of 0.5592/0.5474, RAcc_0.1 of 0.5287/0.5287, RAcc_0.3 of 0.9080/0.9310). Visualizations enabled the localization of residual viable tumor to augment microscopic assessment. CONCLUSION: This work illustrates deep learning's potential for assisting pathological response assessment. Spatial heatmaps and patch examples provide intuitive explanations of model predictions, engendering clinical trust and adoption (Code and data will be available at https://github.com/WinnieLaugh/ESCC_Percentage once the paper has been conditionally accepted). Integrating interpretable computational pathology could help enhance the efficiency and consistency of tumor response assessment and empower precise oncology treatment decisions.

Closed Twisted Hydrogel Ribbons with Self-Sustained Motions under Static Light Irradiation.

Self-sustained motions are widespread in biological systems by harvesting energy from surrounding environments, which inspire scientists to develop autonomous soft robots. However, most-existing soft robots require dynamic heterogeneous stimuli or complex fabrication with different components. Recently, control of topological geometry has been promising to afford soft robots with physical intelligence and thus life-like motions. Reported here are a series of closed twisted ribbon robots, which exhibit self-sustained flipping and rotation under constant light irradiation. Both Möbius strip and Seifert ribbon robots are devised for the first time by using an identical hydrogel, which responds to light irradiation on either side. Experiment and simulation results indicate that the self-regulated motions of the hydrogel robots are related to fast and reversible response of muscle-like gel, self-shadowing effect, and topology-facilitated refresh of light-exposed regions. The motion speeds and directions of the hydrogel robots can be tuned over a wide range. These closed twisted ribbon hydrogels are further applied to execute specific tasks in aqueous environments, such as collecting plastic balls, climbing a vertical rod, and transporting objects. This work presents new design principle for autonomous hydrogel robots by benefiting from material response and topology geometry, which may be inspirative for the robotics community.

Enhanced mechanical and long-lasting antibacterial properties of starch/PBAT blown films via designing of reactive micro-crosslinked starch.

A functional starch (TPS-E) was designed and constructed by incorporating epoxy soybean oil (ESO) and an antibacterial agent polyhexamethylene guanidine hydrochloride (PHMG), then the film was prepared by reaction extrusion and blow molding using TPS-E and poly(butylene adipate-co-terephthalate) (PBAT). The micro-crosslinking structure, forming through ring-opening reaction between the epoxy active site of TPS-E and the end group of PBAT, improved the compatibility of starch/PBAT blend and reduce the dispersed starch phase size, leading to significantly increase the tensile strength. Compared to starch/PBAT films, the tensile strength of TPS-E/PBAT in the longitudinal direction increase by 112% with the same starch content of 30%. Furthermore, these TPS-E/PBAT films demonstrated long-lasting antibacterial performance with a 98% inhibition ratio even after 10 cycles, without any observed leaching of the antibacterial agent, highlighting the high coupling efficiency of PHMG. TPS-E with the degradable ESO also promotes the degradation of PBAT. Thus, an important method of synergistic improving the mechanical, degradable and antibacterial properties of blown films through the design of reactive micro-crosslinked starch structures was established.

Zn Single-Atom Catalysts Enable the Catalytic Transfer Hydrogenation of α,ß-Unsaturated Aldehydes.

Highly active nonprecious-metal single-atom catalysts (SACs) toward catalytic transfer hydrogenation (CTH) of α,ß-unsaturated aldehydes are of great significance but still are deficient. Herein, we report that Zn-N-C SACs containing Zn-N3 moieties can catalyze the conversion of cinnamaldehyde to cinnamyl alcohol with a conversion of 95.5% and selectivity of 95.4% under a mild temperature and atmospheric pressure, which is the first case of Zn-species-based heterogeneous catalysts for the CTH reaction. Isotopic labeling, in situ FT-IR spectroscopy, and DFT calculations indicate that reactants, coabsorbed at the Zn sites, proceed CTH via a "Meerwein-Ponndorf-Verley" mechanism. DFT calculations also reveal that the high activity over Zn-N3 moieties stems from the suitable adsorption energy and favorable reaction energy of the rate-determining step at the Zn active sites. Our findings demonstrate that Zn-N-C SACs hold extraordinary activity toward CTH reactions and thus provide a promising approach to explore the advanced SACs for high-value-added chemicals.

In Situ Imaging of Two-Dimensional Crystal Growth Using a Heat-Resistant Optical Microscope.

Revealing low-dimensional material growth dynamics is critical for crystal growth engineering. However, in a practical high-temperature growth system, the crystal growth process is a black box because of the lack of heat-resistant imaging tools. Here, we develop a heat-resistant optical microscope and embed it in a chemical vapor deposition (CVD) system to investigate two-dimensional (2D) crystal growth dynamics. This in situ optical imaging CVD system can tolerate temperatures of ≤900 °C with a spatial resolution of ∼1 µm. The growth of monolayer MoS2 crystals was studied as a model for 2D crystal growth. The nucleation and growth process have been imaged. Model analysis and simulation have revealed the growth rate, diffusion coefficient, and spatial distribution of the precursor. More importantly, a new vertex-kink-ledge model has been suggested for monolayer crystal growth. This work provides a new technique for in situ microscopic imaging at high temperatures and fundamental insight into 2D crystal growth.

Assessing NGS-based computational methods for predicting transcriptional regulators with query gene sets.

This article provides an in-depth review of computational methods for predicting transcriptional regulators with query gene sets. Identification of transcriptional regulators is of utmost importance in many biological applications, including but not limited to elucidating biological development mechanisms, identifying key disease genes, and predicting therapeutic targets. Various computational methods based on next-generation sequencing (NGS) data have been developed in the past decade, yet no systematic evaluation of NGS-based methods has been offered. We classified these methods into two categories based on shared characteristics, namely library-based and region-based methods. We further conducted benchmark studies to evaluate the accuracy, sensitivity, coverage, and usability of NGS-based methods with molecular experimental datasets. Results show that BART, ChIP-Atlas, and Lisa have relatively better performance. Besides, we point out the limitations of NGS-based methods and explore potential directions for further improvement. Key points: An introduction to available computational methods for predicting functional TRs from a query gene set.A detailed walk-through along with practical concerns and limitations.A systematic benchmark of NGS-based methods in terms of accuracy, sensitivity, coverage, and usability, using 570 TR perturbation-derived gene sets.NGS-based methods outperform motif-based methods. Among NGS methods, those utilizing larger databases and adopting region-centric approaches demonstrate favorable performance. BART, ChIP-Atlas, and Lisa are recommended as these methods have overall better performance in evaluated scenarios.

Heavy metal induced shifts in microbial community composition and interactions with dissolved organic matter in coastal sediments.

Heavy metals can impact the structure and function of coastal sediment. The dissolved organic matter (DOM) pool plays an important role in determining both the heavy metal toxicity and microbial community composition in coastal sediments. However, how heavy metals affect the interactions between microbial communities and DOM remains unclear. Here, we investigated the influence of heavy metals on the microbial community structure (including bacteria and archaea) and DOM composition in surface sediments of Beibu Gulf, China. Our results revealed firstly that chromium, zinc, cadmium, and lead were the heavy metals contributing to pollution in our studied area. Furthermore, the DOM chemical composition was distinctly different in the contaminated area from the uncontaminated area, characterized by a higher average O/C ratio and increased prevalence of carboxyl-rich alicyclic molecules (CRAM) and highly unsaturated compounds (HUC). This indicates that DOM in the contaminated area was more recalcitrant compared to the uncontaminated area. Except for differences in archaeal diversity between the two areas, there were no significant variations observed in the structure of archaea and bacteria, as well as the diversity of bacteria, across the two areas. Nevertheless, our co-occurrence network analysis revealed that the B2M28 and Euryarchaeota, dominating bacterial and archaeal groups in the contaminated area were strongly related to CRAM. The network analysis also unveiled correlations between active bacteria and elevated proportions of nitrogen-containing DOM molecules. In contrast, the archaea-DOM network exhibited strong associations with nitrogen- and sulfur-containing molecules. Collectively, these findings suggest that heavy metals indeed influence the interaction between microbial communities and DOM, potentially affecting the accumulation of recalcitrant compounds in coastal sediments.

Jointly constrained group sparse connectivity representation improves early diagnosis of Alzheimer's disease on routinely acquired T1-weighted imaging-based brain network.

Background: Radiomics-based morphological brain networks (radMBN) constructed from routinely acquired structural MRI (sMRI) data have gained attention in Alzheimer's disease (AD). However, the radMBN suffers from limited characterization of AD because sMRI only characterizes anatomical changes and is not a direct measure of neuronal pathology or brain activity. Purpose: To establish a group sparse representation of the radMBN under a joint constraint of group-level white matter fiber connectivity and individual-level sMRI regional similarity (JCGS-radMBN). Methods: Two publicly available datasets were adopted, including 120 subjects from ADNI with both T1-weighted image (T1WI) and diffusion MRI (dMRI) for JCGS-radMBN construction, 818 subjects from ADNI and 200 subjects solely with T1WI from AIBL for validation in early AD diagnosis. Specifically, the JCGS-radMBN was conducted by jointly estimating non-zero connections among subjects, with the regularization term constrained by group-level white matter fiber connectivity and individual-level sMRI regional similarity. Then, a triplet graph convolutional network was adopted for early AD diagnosis. The discriminative brain connections were identified using a two-sample t-test, and the neurobiological interpretation was validated by correlating the discriminative brain connections with cognitive scores. Results: The JCGS-radMBN exhibited superior classification performance over five brain network construction methods. For the typical NC vs. AD classification, the JCGS-radMBN increased by 1-30% in accuracy over the alternatives on ADNI and AIBL. The discriminative brain connections exhibited a strong connectivity to hippocampus, parahippocampal gyrus, and basal ganglia, and had significant correlation with MMSE scores. Conclusion: The proposed JCGS-radMBN facilitated the AD characterization of brain network established on routinely acquired imaging modality of sMRI. Supplementary Information: The online version of this article (10.1007/s13755-023-00269-0) contains supplementary material, which is available to authorized users.

Bottom-up and top-down controls on Alteromonas macleodii lead to different dissolved organic matter compositions.

The effects of both bottom-up (e.g. substrate) and top-down (e.g. viral lysis) controls on the molecular composition of dissolved organic matter have not been investigated. In this study, we investigated the dissolved organic matter composition of the model bacterium Alteromonas macleodii ATCC 27126 growing on different substrates (glucose, laminarin, extracts from a Synechococcus culture, oligotrophic seawater, and eutrophic seawater), and infected with a lytic phage. The ultra-high resolution mass spectrometry analysis showed that when growing on different substrates Alteromonas macleodii preferred to use reduced, saturated nitrogen-containing molecules (i.e. O4 formula species) and released or preserved oxidized, unsaturated sulfur-containing molecules (i.e. O7 formula species). However, when infected with the lytic phage, Alteromonas macleodii produced organic molecules with higher hydrogen saturation, and more nitrogen- or sulfur-containing molecules. Our results demonstrate that bottom-up (i.e. varying substrates) and top-down (i.e. viral lysis) controls leave different molecular fingerprints in the produced dissolved organic matter.

Simultaneous improvement of thermostability and maltotriose-forming ability of a fungal α-amylase for bread making by directed evolution.

For applications in food industries, a fungal α-amylase from Malbranchea cinnamomea was engineered by directed evolution. Through two rounds of screening, a mutant α-amylase (mMcAmyA) was obtained with higher optimal temperature (70 °C, 5 °C increase) and better hydrolysis properties (18.6 % maltotriose yield, 2.5-fold increase) compared to the wild-type α-amylase (McAmyA). Site-directed mutations revealed that Threonine (Thr) 226 Serine (Ser) substitution was the main reason for the property evolution of mMcAmyA. Through high cell density fermentation, the highest expression level of Thr226Ser was 3951 U/mL. Thr226Ser was further used for bread baking with a dosage of 1000 U/kg flour, resulting in a 17.8 % increase in specific volume and a 35.6 % decrease in hardness compared to the control. The results were a significant improvement on those of McAmyA. Moreover, the mutant showed better anti-staling properties compared to McAmyA, as indicated by the improved sensory evaluation after 4 days of storage at 4 and 25 °C. These findings provide insights into the structure-function relationship of fungal α-amylase and introduce a potential candidate for bread-making industry.

Preparation and adjuvanticity against PCV2 of Viola philippica polysaccharide loaded in Chitosan-Gold nanoparticle.

The present Porcine circovirus type 2 virus (PCV2) vaccine adjuvants suffer from numerous limitations, such as adverse effects, deficient cell-mediated immune responses, and inadequate antibody production. In this study, we explored the potential of a novel nanoparticle (CS-Au NPs) based on gold nanoparticles (Au NPs) and chitosan (CS) that modified Viola philippica polysaccharide (VPP) as efficient adjuvants for PCV2 vaccine. The characterization demonstrated that CS-Au-VPP NPs had a mean particle size of 507.42 nm and a zeta potential value of -21.93 mV. CS-Au-VPP NPs also exhibited good dispersion and a stable structure, which did not alter the polysaccharide properties. Additionally, the CS-Au-VPP NPs showed easy absorption and utilization by the organism. To investigate their immune-enhancing potential, mice were immunized with a mixture of CS-Au-VPP NPs and PCV2 vaccine. The evaluation of relevant immunological indicators, including specific IgG antibodies and their subclasses, cytokines, and T cell subpopulations, confirmed their immune-boosting effects. The in vivo experiments revealed that the medium-dose CS-Au-VPP NPs significantly elevated the levels of specific IgG antibodies and their subclasses, cytokines, and T cell subpopulations in PCV2-immunized mice. These findings suggest that CS-Au-VPP NPs can serve as a promising vaccine adjuvant due to their stable structure and immunoenhancement capabilities.

Protecting against ferroptosis in hyperuricemic nephropathy: The potential of ferrostatin-1 and its inhibitory effect on URAT1.

Hyperuricemic nephropathy (HN) is characterized by renal fibrosis and tubular necrosis caused by elevated uric acid levels. Ferroptosis, an iron-dependent type of cell death, has been implicated in the pathogenesis of kidney diseases. The objective of this study was to explore the role of ferroptosis in HN and the impact of a ferroptosis inhibitor, ferrostatin-1 (Fer-1). The study combined adenine and potassium oxonate administration to establish a HN model in mice and treated HK-2 cells with uric acid to simulate HN conditions. The effects of Fer-1 on the renal function, fibrosis, and ferroptosis-associated molecules were investigated in HN mice and HK-2 cells treated with uric acid. The HN mice presented with renal dysfunction characterized by elevated tissue iron levels and diminished antioxidant capacity. There was a significant decrease in the mRNA and protein expression levels of SLC7A11, GPX4, FTL-1 and FTH-1 in HN mice. Conversely, treatment with Fer-1 reduced serum uric acid, serum creatinine, and blood urea nitrogen, while increasing uric acid levels in urine. Fer-1 administration also ameliorated renal tubule dilatation and reduced renal collagen deposition. Additionally, Fer-1 also upregulated the expression levels of SLC7A11, GPX4, FTL-1, and FTH-1, decreased malondialdehyde and iron levels, and enhanced glutathione in vivo and in vitro. Furthermore, we first found that Fer-1 exhibited a dose-dependent inhibition of URAT1, with the IC50 value of 7.37 ± 0.66 µM. Collectively, the current study demonstrated that Fer-1 effectively mitigated HN by suppressing ferroptosis, highlighting the potential of targeting ferroptosis as a therapeutic strategy for HN.

Norepinephrine versus phenylephrine on cerebral tissue oxygen saturation during prophylactic infusion to prevent spinal hypotension for Caesarean birth.

BACKGROUND: Phenylephrine may cause a reduction in maternal cerebral tissue oxygen saturation (SctO2) during Caesarean birth to prevent spinal hypotension; however, the effect of norepinephrine has not been assessed. We hypothesized that norepinephrine was more effective than phenylephrine in maintaining SctO2 when preventing spinal hypotension during Caesarean birth. METHODS: We conducted a randomized, double-blind, controlled study. Sixty patients were randomly assigned to prophylactic norepinephrine or phenylephrine to maintain blood pressure during spinal anesthesia for Caesarean birth. SctO2, systolic blood pressure, and heart rate were recorded. The primary outcome was the incidence of a 10% reduction of intraoperative SctO2 from baseline or more during Caesarean birth. RESULTS: The norepinephrine group had a lower incidence of more than 10% reduction of intraoperative SctO2 from baseline than that of the phenylephrine group (13.3% vs 40.0%, P = .02). The change in SctO2 after 5 minutes of norepinephrine infusion was higher than that after phenylephrine infusion (-3.4 ±â€…4.7 vs -6.2 ±â€…5.6, P = .04). The change in SctO2 after 10 minutes of norepinephrine infusion was higher than that after phenylephrine infusion (-2.5 ±â€…4.4 vs -5.4 ±â€…4.6, P = .006). The norepinephrine group showed greater left- and right-SctO2 values than the phenylephrine group at 5 to 10 minutes. However, the change in systolic blood pressure was comparable between the 2 groups. CONCLUSION: Norepinephrine was more effective than phenylephrine in maintaining SctO2 when preventing spinal hypotension during Caesarean birth. However, the changes in clinical outcomes caused by differences in SctO2 between the 2 medications warrant further studies.