ExosomePurity: tumour purity deconvolution in serum exosomes based on miRNA signatures.

Exosomes cargo tumour-characterized biomolecules secreted from cancer cells and play a pivotal role in tumorigenesis and cancer progression, thus providing their potential for non-invasive cancer monitoring. Since cancer cell-derived exosomes are often mixed with those from healthy cells in liquid biopsy of tumour patients, accurately measuring the purity of tumour cell-derived exosomes is not only critical for the early detection but also essential for unbiased identification of diagnosis biomarkers. Here, we propose 'ExosomePurity', a tumour purity deconvolution model to estimate tumour purity in serum exosomes of cancer patients based on microribonucleic acid (miRNA)-Seq data. We first identify the differently expressed miRNAs as signature to distinguish cancer cell- from healthy cell-derived exosomes. Then, the deconvolution model was developed to estimate the proportions of cancer exosomes and normal exosomes in serum. The purity predicted by the model shows high correlation with actual purity in simulated data and actual data. Moreover, the model is robust under the different levels of noise background. The tumour purity was also used to correct differential expressed gene analysis. ExosomePurity empowers the research community to study non-invasive early diagnosis and to track cancer progression in cancers more efficiently. It is implemented in R and is freely available from GitHub (https://github.com/WangHYLab/ExosomePurity).

How outdoor horticultural activities affect elderly adults' thermal, physiological and psychological responses: a field study.

We recruited 162 healthy elderly adults to determine the thermal, physiological, and psychological effects of horticultural activities (flower arranging, transplanting, and rubble masonry) in outdoor open spaces. We linked these to local climate conditions, physiology, and comfort through a questionnaire survey. The results showed that: (1) the neutral physiological equivalent temperature (NPET) before the horticultural activities were 22.18 â„ƒ for flower arranging, 23.67 â„ƒ for transplanting, and 20.78 â„ƒ for rubble masonry, while the NPET decreased to 18.53 â„ƒ, 20.73 â„ƒ and 18.04 â„ƒ (respectively) after activities. (2) The heart rate and blood oxygen saturation changed significantly (p < 0.05) only after rubble masonry. (3) The average positive affect (PA) scores increased after flower arranging by 4.83, transplanting by 3.30, and rubble masonry by 4.00. (4) After activities, the thermal sensation vote was mainly influenced by globe temperature (41.36%), air temperature (33.47%), and wind speed (25.17%). Thermal comfort vote could be promoted because of 37.35% of an increasing positive and 21.20% of decreasing negative emotion.

Physiological, Metabolome and Gene Expression Analyses Reveal the Accumulation and Biosynthesis Pathways of Soluble Sugars and Amino Acids in Sweet Sorghum under Osmotic Stresses.

Water scarcity is a major environmental constraint on plant growth in arid regions. Soluble sugars and amino acids are essential osmolytes for plants to cope with osmotic stresses. Sweet sorghum is an important bioenergy crop and forage with strong adaptabilities to adverse environments; however, the accumulation pattern and biosynthesis basis of soluble sugars and amino acids in this species under osmotic stresses remain elusive. Here, we investigated the physiological responses of a sweet sorghum cultivar to PEG-induced osmotic stresses, analyzed differentially accumulated soluble sugars and amino acids after 20% PEG treatment using metabolome profiling, and identified key genes involved in the biosynthesis pathways of soluble sugars and amino acids using transcriptome sequencing. The results showed that the growth and photosynthesis of sweet sorghum seedlings were significantly inhibited by more than 20% PEG. After PEG treatments, the leaf osmotic adjustment ability was strengthened, while the contents of major inorganic osmolytes, including K+ and NO3-, remained stable. After 20% PEG treatment, a total of 119 and 188 differentially accumulated metabolites were identified in the stems and leaves, respectively, and the accumulations of soluble sugars such as raffinose, trehalose, glucose, sucrose, and melibiose, as well as amino acids such as proline, leucine, valine, serine, and arginine were significantly increased, suggesting that these metabolites should play key roles in osmotic adjustment of sweet sorghum. The transcriptome sequencing identified 1711 and 4978 DEGs in the stems, as well as 2061 and 6596 DEGs in the leaves after 20% PEG treatment for 6 and 48 h, respectively, among which the expressions of genes involved in biosynthesis pathways of sucrose (such as SUS1, SUS2, etc.), trehalose (including TPS6), raffinose (such as RAFS2 and GOLS2, etc.), proline (such as P5CS2 and P5CR), leucine and valine (including BCAT2), and arginine (such as ASS and ASL) were significantly upregulated. These genes should be responsible for the large accumulation of soluble sugars and amino acids under osmotic stresses. This study deepens our understanding of the important roles of individual soluble sugars and amino acids in the adaptation of sweet sorghum to water scarcity.

Engineered Collaborative Size Regulation and Shape Engineering of Tremella-Like Au-MnOx for Highly Sensitive Bimodal-Type Lateral Flow Immunoassays.

Engineered collaborative size regulation and shape engineering of multi-functional nanomaterials (NPs) offer extraordinary opportunities for improving the analysis performance. It is anticipated to address the difficulty in distinguishing color changes caused by subtle variations in target concentrations, thereby facilitating the highly sensitive analysis of lateral flow immunoassays (LFIAs). Herein, tremella-like gold-manganese oxide (Au-MnOx ) nanoparticles with precise MnCl2 regulation are synthesized as immuno signal tracers via a facile one-step redox reaction in alkaline condition at ambient temperature. Avail of the tunable elemental composition and anisotropy in morphology, black-colored tremella-like Au-MnOx exhibits superb colorimetric signal brightness, enhanced antibody coupling efficiency, marvelous photothermal performance, and unrestricted immunological recognition affinity, all of which facilitate highly sensitive multi-signal transduction patterns. In conjunction with the handheld thermal reader device, a bimodal-type LFIA that combines size-regulation- and shape-engineering-mediated colorimetric-photothermal dual-response assay (coined as the SSCPD assay) with a limit of detection of 0.012 ng mL-1 for ractopamine (RAC) monitoring is achieved by integrating Au-MnOx with the competitive-type immunoreaction. This work illustrates the effectiveness of this strategy for establishing high-performance sensing, and the SSCPD assay may be extended to a wide spectrum of future point-of-care (POC) diagnostic applications.

Integrated Design of a Dual-Mode Colorimetric Sensor Driven by Enzyme-like Activity Regulation Strategy for Ultratrace and Portable Detection of Hg2.

Colorimetric analysis for mercury detection has great application potential in the prevention of health damage caused by mercury in the environment. Sensitivity, selectivity, and portability are core competencies of sensors, and concentrating these properties in a single sensor for efficient mercury detection remains a great challenge. Herein, a hollow structure CuS@CuSe@PVP (CCP) was prepared in which the enzyme-like activities could be activated by Hg2+ due to the antagonism between Hg and Se, inspiring the establishment of a colorimetric method for Hg2+ detection. As for Hg2+ detection performance, the linear range (LR) and limit of detection (LOD) were 1-900 and 0.81 nM in the POD-like activity system, respectively. Also, 5-550 nM of LR and 2.34 nM of LOD were achieved in the OD-like activity system. Further, a smartphone-mediated portable RGB nanosensor was fabricated, with a LOD down to 6.65 nM in the POD-like system and 7.97 nM in the OD-like system. Moreover, the excellent self-calibration and satisfactory recovery of 94.77%-106.16% were shown in the application of real water samples analysis. This study represented advanced progress toward emerging applications of nanozymes with multiple enzyme-like activities in heavy metal detection and will accelerate the development of efficient and portable heavy metal sensors.

A spectrally discretized wide-angle parabolic equation model for simulating acoustic propagation in laterally inhomogeneous oceans.

Sound waves can be used to carry out underwater activities. Rapidly and accurately simulating sound propagation is the basis for underwater detection. The wide-angle parabolic model has a good computational speed and accuracy and is currently the main numerical model for mid- and low-frequency sound propagation. The classical wide-angle parabolic equation model is discretized by the finite difference method and a low-order difference scheme is generally adopted. In this paper, a wide-angle parabolic equation model based on a spectral method is proposed. The depth operators of each layer are discretized via the Chebyshev spectral method and then assembled into a global matrix for the forward step. Lateral inhomogeneity is addressed by updating the global depth matrix while stepping forward. In the proposed spectral algorithm, both soft and hard seabeds can be accurately simulated by imposing boundary conditions, and the perfectly matched layer technique is used to truncate the unbounded acoustic half-space. Several representative numerical experiments prove the accuracy and efficiency of the proposed algorithm. However, the spectral method requires that the thickness of the layers does not change during the forward step. Thus, the current spectral algorithm cannot simulate waveguides with terrain undulation, which is its main limitation.

Highly Sensitive and Selective Detection of Formaldehyde via Bio-Electrocatalysis over Aldehyde Dehydrogenase.

Formaldehyde (HCHO), as one of the prominent indoor pollutants, causes many health-related problems. Although the detection of HCHO is a widespread concern and a variety of detection methods have been continuously developed, the volatile organic chemical (VOC) interference remains to be solved. Here, we report a highly sensitive and selective method for HCHO detection, relying on the selective electrochemical oxidation of formaldehyde catalyzed by aldehyde dehydrogenases (ALDHs) on a Cu electrode. The detection signal exhibits a standard power law relationship against the analytes with a broad detection range of 10-5-10-15 M and a limit of detection (LOD) of 1.46 × 10-15 M, far below the indoor safe exposure limit (about 10-9 M) for formaldehyde. In comparison to the standard spectrophotometry method, the ALDH-based electrochemical method shows a much high specificity to formaldehyde among common VOCs, such as benzene, toluene, and xylene. This simple yet effective detection technique opens up a new path for developing advanced formaldehyde sensors with high sensitivity and selectivity.

Formation of stable polonium monolayers with tunable semiconducting properties driven by strong quantum size effects.

Elemental two-dimensional (2D) materials have attracted extraordinary interest compared with other 2D materials over the past few years. Fifteen elements from group IIIA to VIA have been discussed experimentally or theoretically for the formation of 2D monolayers, and the remaining few elements still need to be identified. Here, using first-principles calculations within density functional theory (DFT) and ab initio molecular dynamics simulations (AIMDs), we demonstrated that polonium can form stable 2D monolayers (MLs) with a 1T-MoS2-like structure. The band structure calculations revealed that polonium monolayers possess strong semiconducting properties with a band gap of ∼0.9 eV, and such semiconducting properties can well sustain up to a thickness of 4 MLs with a bandgap of ∼0.1 eV. We also found that polonium monolayers can be achieved through a spontaneous phase transition of ultrathin films with magic thicknesses, resulting in a weaker van der Waals interaction of ∼32 meV Å-2 between each three atomic layers. Also, the underlying physics comes from layered Peierls-like distortion driven by strong quantum size effects. Based on these intriguing findings, a suitable substrate on which the polonium monolayer can be grown through an epitaxial growth technique is proposed for further experiments. Our work not only extends completely the puzzle of elemental 2D monolayer materials from group IIIA to VIA, but also presents a new formation mechanism of 2D materials beyond the database of bulk materials with layered van der Waals interactions.

Size and crystal symmetry breaking effects on negative thermal expansion in ScF3 nanostructures.

Nowadays, one of the most typical and important potential applications of negative thermal expansion (NTE) materials is to prepare zero thermal expansion or controllable coefficient thermal expansion materials by compounding them with positive thermal expansion materials. The research on NTE properties at the nanoscales is the basis and premise for the realization of high-quality composites. Here, using first-principles calculations, we take a typical open framework material ScF3 as an example to study a new NTE mechanism at the nanoscale, which involves edge and size effects, as well as crystal symmetry breaking. By analyzing the vibrational modes in ultrathin ScF3 films, three effects contributing to the NTE properties are identified, namely, the acoustic mode (ZA mode) induced by surface truncation, the enhanced rotations of ScF6 octahedra in the surface layer and the suppressed rotations of ScF6 octahedra in the inner layer due to crystal symmetry breaking. With increasing thickness, the effect of the ZA mode vibration gradually weakens, while the rotations of the ScF6 octahedra in the surface and inner layers are enhanced. Ultimately, the approximately mutual compensation of these three effects makes the NTE coefficients of different thicknesses almost unchanged. Finally, we simply generalize our conclusions to zero dimensional nanoparticles. This work reveals a new NTE mechanism in low-dimensional open framework materials, which serves as a guide in designing NTE materials at the nanoscale.

A dual-responsive colorimetric probe for the detection of Cu2+ and Ni2+ species in real water samples and human serum.

The monitoring of heavy transition metals has increasingly attracted great attention because they pollute the environment and have unique physiological functions. Chemosensors are useful tools for monitoring heavy transition metals due to their simple visualization, excellent sensitivity and high selectivity. Herein, we have developed a novel chemosensor for the detection of water-soluble Cu2+ and Ni2+ species with different mechanisms, and low detection limits of 2.1 nM for Cu2+ and 1.2 nM for Ni2+ were obtained. The colorimetric probe CPH has been applied to qualitative and quantitative detection of Cu2+ and Ni2+ species in real samples.

moPPIt: De Novo Generation of Motif-Specific Binders with Protein Language Models.

The ability to precisely target specific motifs on disease-related proteins, whether conserved epitopes on viral proteins, intrinsically disordered regions within transcription factors, or breakpoint junctions in fusion oncoproteins, is essential for modulating their function while minimizing off-target effects. Current methods struggle to achieve this specificity without reliable structural information. In this work, we introduce a motif-specific PPI targeting algorithm, moPPIt, for de novo generation of motif-specific peptide binders from the target protein sequence alone. At the core of moPPIt is BindEvaluator, a transformer-based model that interpolates protein language model embeddings of two proteins via a series of multi-headed self-attention blocks, with a key focus on local motif features. Trained on over 510,000 annotated PPIs, BindEvaluator accurately predicts target binding sites given protein-protein sequence pairs with a test AUC > 0.94, improving to AUC > 0.96 when fine-tuned on peptide-protein pairs. By combining BindEvaluator with our PepMLM peptide generator and genetic algorithm-based optimization, moPPIt generates peptides that bind specifically to user-defined residues on target proteins. We demonstrate moPPIt's efficacy in computationally designing binders to specific motifs, first on targets with known binding peptides and then extending to structured and disordered targets with no known binders. In total, moPPIt serves as a powerful tool for developing highly specific peptide therapeutics without relying on target structure or structure-dependent latent spaces.

Recent advances of small molecule detection in nanopore sensing.

Due to its advantages of label-free and highly sensitive, the resistive pulse sensing with a nanopore has recently become even more potent for the discrimination of analytes in single molecule level. Generally, a transient interruption of ion current originated from the captured molecule passing through a nanopore will provide the rich information on the structure, charge and translocation dynamics of the analytes. Therefore, nanopore sensors have been widely used in the fields of DNA sequencing, protein recognition, and the portable detection of varied macromolecules and particles. However, the conventional nanopore devices are still lack of sufficient selectivity and sensitivity to distinguish more metabolic molecules involving ATP, glucose, amino acids and small molecular drugs because it is hard to receive a large number of identifiable signals with the fabricated pores comparable in size to small molecules for nanopore sensing. For all this, a series of innovative strategies developed in the past decades have been summarized in this review, including host-guest recognition, engineering alteration of protein channel, the introduction of nucleic acid aptamers and various delivery carriers integrating signal amplification sections based on the biological and solid nanopore platforms, to achieve the high resolution for the small molecules sensing in micro-nano environment. These works have greatly enhanced the powerful sensing capabilities and extended the potential application of nanopore sensors.

Advances of the MAPK pathway in the treatment of spinal cord injury.

Spinal cord injury (SCI) represents a complex pathology within the central nervous system (CNS), leading to severe sensory and motor impairments. It activates various signaling pathways, notably the mitogen-activated protein kinase (MAPK) pathway. Present treatment approaches primarily focus on symptomatic relief, lacking efficacy in addressing the underlying pathophysiological mechanisms. Emerging research underscores the significance of the MAPK pathway in neuronal differentiation, growth, survival, axonal regeneration, and inflammatory responses post-SCI. Modulating this pathway post-injury has shown promise in attenuating inflammation, minimizing apoptosis, alleviating neuropathic pain, and fostering neural regeneration. Given its pivotal role, the MAPK pathway emerges as a potential therapeutic target in SCI management. This review synthesizes current knowledge on SCI pathology, delineates the MAPK pathway's characteristics, and explores its dual roles in SCI pathology and therapeutic interventions. Furthermore, it addresses the existing challenges in MAPK research in the context of SCI, proposing solutions to overcome these hurdles. Our aim is to offer a comprehensive reference for future research on the MAPK pathway and SCI, laying the groundwork for targeted therapeutic strategies.

Genome-wide identification and phylogenetic analysis of the tetraspanin gene family in lepidopteran insects and expression profiling analysis in Helicoverpa armigera.

The tetraspanin gene family encodes cell-surface proteins that span the membrane 4 times and play critical roles in a wide range of biological processes across numerous organisms. Recent findings highlight the involvement of a tetraspanin of the lepidopteran pest Helicoverpa armigera in resistance to Bacillus thuringiensis Cry insecticidal proteins, which are extensively used in transgenic crops. Thus, a better understanding of lepidopteran tetraspanins is urgently needed. In the current study, genome scanning in 10 lepidopteran species identified a total of 283 sequences encoding potential tetraspanins. Based on conserved cysteine patterns in the large extracellular loop and their phylogenetic relationships, these tetraspanins were classified into 8 subfamilies (TspA to TspH). Six ancestral introns were identified within lepidopteran tetraspanin genes. Tetraspanins in TspA, TspB, TspC, and TspD subfamilies exhibit highly similar gene organization, while tetraspanins in the remaining 4 subfamilies exhibited variation in intron loss and/or gain during evolution. Analysis of chromosomal distribution revealed a lepidopteran-specific cluster of 10 to 11 tetraspanins, likely formed by tandem duplication events. Selective pressure analysis indicated negative selection across all orthologous groups, with ω values ranging between 0.004 and 0.362. However, positive selection was identified at 18 sites within TspB5, TspC5, TspE3, and TspF10. Furthermore, spatiotemporal expression analysis of H. armigera tetraspanins demonstrated variable expression levels across different developmental stages and tissues, suggesting diverse functions of tetraspanin members in this globally important insect pest. Our findings establish a solid foundation for subsequent functional investigations of tetraspanins in lepidopteran species.

Bioinspired Hierarchical Self-Assembled Nanozyme for Efficient Antibacterial Treatment.

Along with the rapid development and ever-deepening understanding of nanoscience and nanotechnology, nanomaterials hold promise to mimic the highly evolved biological exquisite nanostructures and sophisticated functions. Here, inspired by the ubiquitous antibacterial nanostructures on the wing surfaces of some insects, a NiCo2 O4 nanozyme with self-adaptive hierarchical nanostructure is developed that can capture bacteria of various morphotypes via the physico-mechanical interaction between the nanostructure and bacteria. Moreover, the developed biomimetic nanostructure further exhibits superior peroxidase-like catalytic activity, which can catalytically generate highly toxic reactive oxygen species that disrupt bacterial membranes and induce bacterial apoptosis. Therefore, the mechano-catalytic coupling property of this NiCo2 O4 nanozyme allows for an extensive and efficient antibacterial application, with no concerns of antimicrobial resistance. This work suggests a promising strategy for the rational design of advanced antibacterial materials by mimicking biological antibiosis.

Fucoidan improving spinal cord injury recovery: Modulating microenvironment and promoting remyelination.

INTRODUCTION: Excessive neuroinflammation, apoptosis, glial scar, and demyelination triggered by spinal cord injury (SCI) are major obstacles to SCI repair. Fucoidan, a natural marine plant extract, possesses broad-spectrum anti-inflammatory and immunomodulatory effects and is regarded as a potential therapeutic for various diseases, including neurological disorders. However, its role in SCI has not been investigated. METHODS: In this study, we established an SCI model in mice and intervened in injury repair by daily intraperitoneal injections of different doses of fucoidan (10 and 20 mg/kg). Concurrently, primary oligodendrocyte precursor cells (OPCs) were treated in vitro to validate the differentiation-promoting effect of fucoidan on OPCs. Basso Mouse Scale (BMS), Louisville Swim Scale (LSS), and Rotarod test were carried out to measure the functional recovery. Immunofluorescence staining, and transmission electron microscopy (TEM) were performed to assess the neuroinflammation, apoptosis, glial scar, and remyelination. Western blot analysis was conducted to clarify the underlying mechanism of remyelination. RESULTS: Our results indicate that in the SCI model, fucoidan exhibits significant anti-inflammatory effects and promotes the transformation of pro-inflammatory M1-type microglia/macrophages into anti-inflammatory M2-type ones. Fucoidan enhances the survival of neurons and axons in the injury area and improves remyelination. Additionally, fucoidan promotes OPCs differentiation into mature oligodendrocytes by activating the PI3K/AKT/mTOR pathway. CONCLUSION: Fucoidan improves SCI repair by modulating the microenvironment and promoting remyelination.

Morphological and molecular response mechanisms of the root system of different Hemarthria compressa species to submergence stress.

Introduction: The severity of flood disasters is increasing due to climate change, resulting in a significant reduction in the yield and quality of forage crops worldwide. This poses a serious threat to the development of agriculture and livestock. Hemarthria compressa is an important high-quality forage grass in southern China. In recent years, frequent flooding has caused varying degrees of impacts on H. compressa and their ecological environment. Methods: In this study, we evaluated differences in flooding tolerance between the root systems of the experimental materials GY (Guang Yi, flood-tolerant) and N1291 (N201801291, flood-sensitive). We measured their morphological indexes after 7 d, 14 d, and 21 d of submergence stress and sequenced their transcriptomes at 8 h and 24 h, with 0 h as the control. Results: During submergence stress, the number of adventitious roots and root length of both GY and N1291 tended to increase, but the overall growth of GY was significantly higher than that of N1291. RNA-seq analysis revealed that 6046 and 7493 DEGs were identified in GY-8h and GY-24h, respectively, and 9198 and 4236 DEGs in N1291-8h and N1291-24h, respectively, compared with the control. The GO and KEGG enrichment analysis results indicated the GO terms mainly enriched among the DEGs were oxidation-reduction process, obsolete peroxidase reaction, and other antioxidant-related terms. The KEGG pathways that were most significantly enriched were phenylpropanoid biosynthesis, plant hormone signal transduction etc. The genes of transcription factor families, such as C2H2, bHLH and bZIP, were highly expressed in the H. compressa after submergence, which might be closely related to the submergence adaptive response mechanisms of H. compressa. Discussion: This study provides basic data for analyzing the molecular and morphological mechanisms of H. compressa in response to submergence stress, and also provides theoretical support for the subsequent improvement of submergence tolerance traits of H. compressa.

Multistate, Ultrathin, Back-End-of-Line-Compatible AlScN Ferroelectric Diodes.

The growth in data generation necessitates efficient data processing technologies to address the von Neumann bottleneck in conventional computer architecture. Memory-driven computing, which integrates nonvolatile memory (NVM) devices in a 3D stack, is gaining attention, with CMOS back-end-of-line (BEOL)-compatible ferroelectric (FE) diodes being ideal due to their two-terminal design and inherently selector-free nature, facilitating high-density crossbar arrays. Here, we demonstrate BEOL-compatible, high-performance FE diodes scaled to 5, 10, and 20 nm FE Al0.72Sc0.28N/Al0.64Sc0.36N films. Through interlayer (IL) engineering, we show substantial improvements in the on/off ratios (>166 times) and rectification ratios (>176 times) in these scaled devices. These characteristics also enable 5-bit multistate operation with a stable retention. We also experimentally and theoretically demonstrate the counterintuitive result that the inclusion of an IL can lead to a decrease in the ferroelectric switching voltage of the device. An in-depth analysis into the device transport mechanisms is performed, and our compact model aligns seamlessly with the experimental results. Our results suggest the possibility of using scaled AlxSc1-xN FE diodes for high-performance, low-power, embedded NVM.

DLP fabrication of HA scaffold with customized porous structures to regulate immune microenvironment and macrophage polarization for enhancing bone regeneration.

The immune microenvironment plays a pivotal role in osteoanagenesis. Biomaterials can modulate osteogenic efficacy by inducing specific local immune reactions. As 3D-printing technology advances, digital light projection printing has emerged as a promising method for creating large scale, high-precision biomaterial scaffolds. By adjusting the solid content and the sintering conditions during printing, the pore size of biomaterials can be meticulously controlled. Yet, the systematic influence of pore size on the immune microenvironment remains uncharted. We fabricated 3D-printed hydroxyapatite bioceramic scaffolds with three distinct pore sizes: 400 µm, 600 µm, and 800 µm. Our study revealed that scaffolds with a pore size of 600 µm promote macrophage M2 polarization, which is achieved by upregulating interferon-beta and HIF-1α production. When these materials were implanted subcutaneously in rats and within rabbit skulls, we observed that the 600 µm scaffolds notably improved the long-term inflammatory response, fostered vascular proliferation, and augmented new bone growth. This research paves the way for innovative therapeutic strategies for treating large segmental bone defects in clinical settings.

An investigation into the HIF-dependent intestinal barrier protective mechanism of Qingchang Wenzhong decoction in ulcerative colitis management.

ETHNOPHARMACOLOGICAL RELEVANCE: Ulcerative colitis (UC) is a chronic, non-specific inflammatory disease affecting the colon and rectum with an etiology that remains elusive. Traditional Chinese medicine (TCM) has been widely used on long-term UC treatment to better maintain the efficacy than traditional aminosalicylic acid or glucocorticosteroids and to ease financial burden of patients. Qingchang Wenzhong Decoction (QCWZD) is a modern TCM decoction with established clinical efficacy but the mechanism of its protection on intestinal barrier function remains unclear. AIM OF THE STUDY: Current findings highlight that the activation of the hypoxia inducible factor (HIF) pathway can facilitate the repair of intestinal epithelium barrier. This study is to investigate the protective effects of QCWZD and its HIF-targeted ingredients on hypoxia-dependent intestinal barrier. METHODS: The mice model of UC was induced by dextran sulfate sodium (DSS). Disease activity index (DAI) and histopathology scores and colon length were used to measure the severity of colitis. The DAO activity in serum and protein expression of tight junction (TJ) proteins were detected to explore the function of intestinal barrier. The protein levels of HIF-1α and its downstream gene heme oxygenase-1 (HO-1) were measured as well. HIF-targeted active ingredients in QCWZD were selected by network pharmacology and molecular docking. Protective effects of six constituents on HIF-related anti-oxidative and barrier protective pathway were evaluated by lipopolysaccharide (LPS)-induced HT29 and RAW264.7 cells, through the measurement of the production of ROS and mRNA level of pro-inflammatory cytokines. HIF-1α knockdown was carried out to explore the correlation of protection effects with HIF-related pathway of the active ingredients. RESULTS: QCWZD effectively alleviated colitis induced by DSS and demonstrated a protective effect on intestinal barrier function by upregulating HIF-related pathways. Six specific ingredients in QCWZD, targeting HIF, successfully reduced the production of cellular ROS and proinflammatory cytokines in LPS-induced cells. It is noteworthy that the barrier protection provided by these molecules is intricately linked with the HIF-related pathway. CONCLUSIONS: This study elucidates the HIF-related molecular mechanism of QCWZD in protecting the function of the epithelial barrier. Six compounds targeting the activation of the HIF-dependent pathway were demonstrated to unveil a novel therapeutic approach for managing UC.