Directed Differentiation of Human Induced Pluripotent Stem Cells to Heart Valve Cells.

BACKGROUND: A main obstacle in current valvular heart disease research is the lack of high-quality homogeneous functional heart valve cells. Human induced pluripotent stem cells (hiPSCs)-derived heart valve cells may help with this dilemma. However, there are no well-established protocols to induce hiPSCs to differentiate into functional heart valve cells, and the networks that mediate the differentiation have not been fully elucidated. METHODS: To generate heart valve cells from hiPSCs, we sequentially activated the Wnt, BMP4, VEGF (vascular endothelial growth factor), and NFATc1 signaling pathways using CHIR-99021, BMP4, VEGF-165, and forskolin, respectively. The transcriptional and functional similarity of hiPSC-derived heart valve cells compared with primary heart valve cells were characterized. Longitudinal single-cell RNA sequencing was used to uncover the trajectory, switch genes, pathways, and transcription factors of the differentiation. RESULTS: An efficient protocol was developed to induce hiPSCs to differentiate into functional hiPSC-derived valve endothelial-like cells and hiPSC-derived valve interstitial-like cells. After 6-day differentiation and CD144 magnetic bead sorting, ≈70% CD144+ cells and 30% CD144- cells were obtained. On the basis of single-cell RNA sequencing data, the CD144+ cells and CD144- cells were found to be highly similar to primary heart valve endothelial cells and primary heart valve interstitial cells in gene expression profile. Furthermore, CD144+ cells had the typical function of primary heart valve endothelial cells, including tube formation, uptake of low-density lipoprotein, generation of endothelial nitric oxide synthase, and response to shear stress. Meanwhile, CD144- cells could secret collagen and matrix metalloproteinases, and differentiate into osteogenic or adipogenic lineages like primary heart valve interstitial cells. Therefore, we identified CD144+ cells and CD144- cells as hiPSC-derived valve endothelial-like cells and hiPSC-derived valve interstitial-like cells, respectively. Using single-cell RNA sequencing analysis, we demonstrated that the trajectory of heart valve cell differentiation was consistent with embryonic valve development. We identified the main switch genes (NOTCH1, HEY1, and MEF2C), signaling pathways (TGF-ß, Wnt, and NOTCH), and transcription factors (MSX1, SP5, and MECOM) that mediated the differentiation. Finally, we found that hiPSC-derived valve interstitial-like cells might derive from hiPSC-derived valve endothelial-like cells undergoing endocardial-mesenchymal transition. CONCLUSIONS: In summary, this is the first study to report an efficient strategy to generate functional hiPSC-derived valve endothelial-like cells and hiPSC-derived valve interstitial-like cells from hiPSCs, as well as to elucidate the differentiation trajectory and transcriptional dynamics of hiPSCs differentiated into heart valve cells.

Ultrabright Green-Emissive Nanodots for Precise Biological Visualization.

Developing general methods to fabricate water-dispersible and biocompatible fluorescent probes will promote different biological visualization applications. Herein, we report a metal-facilitated method to fabricate ultrabright green-emissive nanodots via the one-step solvothermal treatment of rose bengal, ethanol, and various metal ions. These metal-doped nanodots show good water dispersity, ultrahigh photoluminescence quantum yields (PLQYs) (e.g., the PLQY of Fe-doped nanodots (FeNDs) was ∼97%), and low phototoxicity. Owing to the coordination effect of metal ions, the FeNDs realize glutathione detection with outstanding properties. Benefiting from the high endoplasmic reticulum (ER) affinity of the chloride group, the FeNDs can act as an ER tracker with long ER imaging capacity (FeNDs: >24 h; commercial ER tracker: ∼1 h) and superb photostability and can achieve tissue visualization in living Caenorhabditis elegans. The metal-doped nanodots represent a general nanodot preparation method and may shed new light on diverse biological visualization uses.

Iridium-Catalyzed Oxidant-Free Transfer Dehydrogenation of Carboxylic Acids.

Direct dehydrogenation of carboxylic acids to their unsaturated counterparts represents a valuable transformation for complex molecule synthesis, which, however, has been challenging to achieve. In addition, the current carbonyl desaturation methods are almost all based on oxidative conditions. Here we report an Ir-catalyzed redox-neutral transfer dehydrogenation approach to directly convert carboxylic acids to either α,ß- or ß,γ-unsaturated counterparts. These reactions avoid using oxidants or strong bases, thus, tolerating various functional groups. The combined experimental and computational mechanistic studies suggest that this transfer hydrogenation reaction involves directed C-H oxidative addition, ß-H elimination, and dihydride transfer to an alkene acceptor with C(sp3)-H reductive elimination as the turnover-limiting step.

Boosting Efficient Alkaline Hydrogen Evolution Reaction of CoFe-Layered Double Hydroxides Nanosheets via Co-Coordination Mechanism of W-Doping and Oxygen Defect Engineering.

While surface defects and heteroatom doping exhibit promising potential in augmenting the electrocatalytic hydrogen evolution reaction (HER), their performance remains unable to rival that of the costly Pt-based catalysts. Yet, the concurrent modification of catalysts by integrating both approaches stands as a promising strategy to effectively address the aforementioned limitation. In this work, tungsten dopants are introduced into self-supported CoFe-layered double hydroxides (LDH) on nickel foam using a hydrothermal method, and oxygen vacancies (Ov) are further introduced through calcination. The analysis results demonstrated that tungsten doping reduces the Ov formation energy of CoFeW-LDH. The Ov acted as oxophilic sites, facilitating water adsorption and dissociation, and reducing the barrier for cleaving HO─H bonds from 0.64 to 0.14 eV. Additionally, Ov regulated the electronic structure of CoFeW-LDH to endow optimized hydrogen binding ability on tungsten atoms, thereby accelerating alkaline Volmer and Heyrovsky reaction kinetics. Specifically, the abundance of Ov induced a transition of tungsten from a six-coordinated to highly active four-coordinated structure, which becomes the active site for HER. Consequently, an ultra-low overpotential of 41 mV at 10 mA cm-2, and a low Tafel slope of 35 mV dec-1 are achieved. These findings offer crucial insights for the design of efficient HER electrocatalysts.

Wideband finely tunable, ultralow-phase noise microwave generation in a Brillouin cavity.

A novel, to the best of our knowledge, approach to generate frequency-tunable microwave sources with low-phase-noise based on a Brillouin laser frequency comb is proposed and experimentally demonstrated. The Brillouin laser frequency comb is generated by combining stimulated Brillouin scattering, frequency shifting optical injection locking, modulation sideband optical injection locking (MSOIL), and four-wave mixing effects. By beating the generated comb lines, the microwave is generated with an extremely low-level phase noise of -120 dBc/Hz at a 10-kHz offset. The frequency of the microwave signal can be finely tuned in steps of a Brillouin cavity mode spacing (i.e., 2 MHz) and coarsely adjusted to integer times the applied RF signal frequency in the MSOIL unit. Remarkably, the phase noise of the microwave source can be kept at almost the same low level during the whole tuning process over the frequency range of 30-75 GHz. The proposed tunable low-phase-noise microwave generation approach has great potential applications in communications, radars, and metrology.

Precise selection and amplification of a single comb line from femtosecond mode-locked lasers.

We propose and demonstrate a novel, to the best of our knowledge, scheme for extracting and amplifying a single comb line with a high signal-to-noise ratio (SNR) from a femtosecond mode-locked laser (FMLL). The scheme is realized based on the combination of pulse repetition-rate multiplication, optical injection locking, and the polarization-pulling-attributes of stimulated Brillouin scattering. The SNR of the selected and amplified comb line is more than 70 dB, and its frequency can be tuned at an arbitrary comb line position over the whole range of the FMML. The white frequency noise floor measured through a delayed self-heterodyne interferometry technique is around 80 Hz2/Hz. The scheme presented in this work has shown the potential for many applications such as ultra-precision metrology and spectroscopy.

Changing epidemiology of inflammatory bowel disease in children and adolescents.

BACKGROUND: The incidence of inflammatory bowel disease (IBD) is rising worldwide, but epidemiological data on children and adolescents are lacking. Understanding the global burden of IBD among children and adolescents is essential for global standardization of methodology and treatment options. METHODS: This is a cross-sectional study based on aggregated data. We estimated the prevalence and incidence of IBD in children and adolescents between 1990 and 2019 according to the Global Burden of Disease Study 2019 (GBD 2019). Age-standardized rates (ASRs) and estimated annual percentage changes (EAPCs) were used to compare the burden and trends between different regions and countries. RESULTS: In 2019, there were 25,659 new cases and 88,829 prevalent cases of IBD among children and adolescents globally, representing an increase of 22.8% and 18.5%, respectively, compared to 1990. Over the past 30 years, the incidence and prevalence of IBD among children and adolescents have been highest in high SDI regions, with the most significant increases in East Asia and high-income Asia Pacific. At the age level, incidence and prevalence were significantly higher in the 15-19-year-old age group, while the < 5-year-old group showed the most significant increase in incidence and prevalence. CONCLUSION: The incidence of IBD in children and adolescents is significantly on the rise in some countries and regions, and IBD will remain an important public health issue with extensive healthcare and economic costs in the future. The reported IBD burden in children and adolescents at the global, regional, and national levels will assist in the development of more precise health policies.

Childhood Gender Nonconformity and Parental Maltreatment as Mediators of Sexual Orientation Disparities in Childhood Emotional and Behavioral Difficulties.

The mechanisms underlying sexual orientation differences in psychopathology originating in childhood remain understudied since sexual orientation does not directly manifest in childhood. This study tested whether childhood gender nonconformity and parental maltreatment before age 6 years 9 months partly explained sexual orientation disparities in the developmental trajectories of emotional and behavioral difficulties from age 6 years 9 months to 11 years 8 months. The Avon Longitudinal Study of Parents and Children was used (2182 boys and 2422 girls, Mage = 15.5, 90% White). After controlling for early life factors, non-heterosexual boys and girls displayed significantly greater emotional and behavioral difficulties than their heterosexual counterparts at all three ages. There was a sex difference in the mediating effects. For girls, sexual orientation disparities in childhood emotional and behavioral difficulties were partially explained by childhood gender nonconformity. For boys, sexual orientation disparities in childhood emotional and behavioral difficulties were partially explained by a path through greater childhood gender nonconformity, leading to increased risk of being the targets of parental maltreatment. Childhood gender nonconformity, parental maltreatment, and other early life factors only partially explain sexual orientation disparities in childhood emotional and behavioral difficulties. The mediating effects of childhood gender nonconformity and parental maltreatment on the association between sexual orientation and childhood emotional and behavioral difficulties differ between the sexes.

Melt-electrowriting-enabled anisotropic scaffolds loaded with valve interstitial cells for heart valve tissue Engineering.

Tissue engineered heart valves (TEHVs) demonstrates the potential for tissue growth and remodel, offering particular benefit for pediatric patients. A significant challenge in designing functional TEHV lies in replicating the anisotropic mechanical properties of native valve leaflets. To establish a biomimetic TEHV model, we employed melt-electrowriting (MEW) technology to fabricate an anisotropic PCL scaffold. By integrating the anisotropic MEW-PCL scaffold with bioactive hydrogels (GelMA/ChsMA), we successfully crafted an elastic scaffold with tunable mechanical properties closely mirroring the structure and mechanical characteristics of natural heart valves. This scaffold not only supports the growth of valvular interstitial cells (VICs) within a 3D culture but also fosters the remodeling of extracellular matrix of VICs. The in vitro experiments demonstrated that the introduction of ChsMA improved the hemocompatibility and endothelialization of TEHV scaffold. The in vivo experiments revealed that, compared to their non-hydrogel counterparts, the PCL-GelMA/ChsMA scaffold, when implanted into SD rats, significantly suppressed immune reactions and calcification. In comparison with the PCL scaffold, the PCL-GelMA/ChsMA scaffold exhibited higher bioactivity and superior biocompatibility. The amalgamation of MEW technology and biomimetic design approaches provides a new paradigm for manufacturing scaffolds with highly controllable microstructures, biocompatibility, and anisotropic mechanical properties required for the fabrication of TEHVs.

Ultra-compact, low-loss,TE0- and TE1-compatible mode waveguide bends.

Waveguide bends have become an interesting research direction because they allow highly curved light transmission in a limited space. Here, we propose waveguide bends supporting two TE modes by etching slots and adding germanium arcs in the inner side of a waveguide bend. Simulations show that the bending radius of our proposed base-mode T E 0 waveguide bend drops to 500 nm and its insertion loss (IL) is reduced to 0.13 dB with footprints as small as 0.75µm×0.75µm. For the higher-order T E 1 mode waveguide bend, we adjust the introduced structure in combination with the light field distribution. The IL of the waveguide bend is also reduced to 0.18 dB with footprints as small as 1.85µm×1.85µm. T E 0 mode has 410 nm bandwidth in the optical communication band while T E 1 mode has 330 nm bandwidth by keeping I L<0.5d B. Through the analysis of these structural characteristics, we believe that this method still has great potential in higher-order mode transmission.

Low loss and ultra-broadband design of an integrated 3 dB power splitter centered at 2 µm.

Because chemical gas is sensitive to absorption in the 2 µm band, and 2 µm matches the absorption band of the remote sensing material, many remote sensors and optical sensors are designed to operate in the 2 µm wavelength region. In this paper, we designed an integrated 3 dB power splitter centered at 2 µm. The study of this device is built on a silicon-on-insulator (SOI) platform. We introduced a subwavelength grating (SWG) to improve the performance of the device. We used the three-dimensional finite-difference time-domain (3D FDTD) method to analyze the effect of the structure on the power splitter. The insertion loss (IL) of the fundamental TE mode is only 0.04 dB at 2 µm and its bandwidth of IL <0.45d B is 940 nm (1570-2510 nm). It is suitable for multidomain and all-band photonic integrated circuits at 2 µm.

Discovery of a Highly Promising Disulfide Derivative Scaffold as Inhibitor of SARS-CoV-2 main protease.

The main protease (Mpro) of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) represents a promising target for antiviral drugs aimed at combating COVID-19. Consequently, the development of Mpro inhibitor  is an ideal strategy for combating the virus. In this study, we identified twenty-two dithiocarbamates (1a-h), dithiocarbamate-Cu(II) complexes (2a-hCu) and disulfide derivatives (2a-e, 2i) as potent inhibitors of Mpro, with IC50 value range of 0.09-0.72, 0.9-24.7 and 15.1-111 µM, respectively, through FRET screening. The enzyme kinetics, inhibition mode, jump dilution, and DTT assay revealed that 1g may be a partial reversible inhibitor, while 2d and 2f-Cu are the irreversible and dose- and time-dependent inhibitors, potentially covalently binding to the target. Binding of 2d, 2f-Cu and 1g to Mpro was found to decrease the stability of the protein. Additionally, DTT assays and thermal shift assays indicated that 2f-Cu and 2d are the nonspecific and promiscuous cysteine protease inhibitor. ICP-MS implied that the inhibitory activity of 2f-Cu may stem from the uptake of Cu(II) by the enzyme. Cytotoxicity assays demonstrated that 2d and 1g exhibit low cytotoxicity, whereas 2f-Cu show certain cytotoxicity in L929 cells. Overall, this work presents two promising scaffolds for the development of Mpro inhibitors to combat COVID-19.

Risk factors for surgical site infection after percutaneous endoscopic lumbar discectomy.

The objective of this study was to investigate the risk factors associated with surgical site infection (SSI) after percutaneous endoscopic lumbar discectomy (PELD) in patients with lumbar disc herniation (LDH). A retrospective analysis was performed on a cohort of 335 patients who underwent PELD between January 2016 and January 2023. Data were derived from the Hospital Information System (HIS), and a comprehensive statistical assessment was performed using IBM SPSS Statistics version 25.0. Both univariate and multivariate logistic regression analyses assessed a range of risk determinants, such as age, body mass index (BMI), comorbidities, laboratory test parameters and surgery-related variables. The incidence of SSI after PELD was 2.7% (9/335). Univariate analysis highlighted BMI, diabetes mellitus, long-term corticosteroid consumption, surgical time and cerebrospinal fluid leakage as significant predictors of SSI. Multivariate logistic regression identified BMI, diabetes mellitus, long-term corticosteroid consumption, surgical time and cerebrospinal fluid leakage as significant risk factors for SSI after PELD. High BMI, diabetes mellitus, long-term corticosteroid consumption, long surgical time and postoperative cerebrospinal fluid leakage are predisposing factors for SSI in patients undergoing PELD. Precise interventions focused on such risk components, including careful preoperative assessment and strategic postoperative care, are essential to reduce the incidence of SSI and improve surgical efficacy.

Childhood Gender Nonconformity and Sexual Orientation Disparities in Depressive Symptoms: The Role of Parental Attitudes.

Purpose: This study tested whether sexual orientation disparities in depressive symptoms are partially explained by recalled childhood gender nonconformity and whether the proportion of this association explained by childhood gender nonconformity is moderated by recalled parental attitudes toward childhood gender nonconformity. Methods: A convenience sample of young adults was recruited from two Chinese online survey platforms (272 heterosexual males, 272 bisexual males, 272 gay males, 272 heterosexual females, 272 bisexual females, and 272 lesbian females). Both mediation and moderated mediation models were conducted. Results: For both sexes, bisexual and gay/lesbian individuals reported significantly higher levels of depressive symptoms than heterosexual individuals, with total effects (standardized path coefficients) ranging from 0.25 to 0.38, all ps < 0.01. These sexual orientation disparities in depressive symptoms were partially explained by childhood gender nonconformity, with indirect effects ranging from 0.08 to 0.17, all ps < 0.001. The effect of childhood gender nonconformity on depressive symptoms was significantly moderated by parental attitudes. The mediating effect of childhood gender nonconformity on sexual orientation disparities in depressive symptoms was strongest at the more negative levels (one standard deviation [SD] above the mean) of parental attitudes and weakest at more tolerant levels (one SD below the mean) of parental attitudes. Conclusions: Childhood gender nonconformity may be a partial contributor to sexual orientation disparities in depressive symptoms and this indirect effect may be moderated by parental attitudes toward childhood gender nonconformity, with the indirect effect decreasing when parental attitudes move from negative toward more tolerant levels.

Highly efficient degradation of tetracycline in groundwater by nanoscale zero-valent iron-copper bimetallic biochar: active [H] attack and direct electron transfer mechanism.

Development of carbon materials with high activity was important for rapid degradation of emerging pollutants. In this paper, a novel nanoscale zero-valent iron-copper bimetallic biochar (nZVIC-BC) was synthesized by carbothermal reduction of waste pine wood and copper-iron layered double hydroxides (LDHs). Characterization and analysis of its structural, elemental, crystalline, and compositional aspects using XRD, FT-IR, SEM, and TEM confirmed the successful preparation of nZVIC-BC and the high dispersion of Fe-Cu nanoparticles in an ordered carbon matrix. The experimental results showed that the catalytic activity of nZVIC-BC (Kobs of 0.0219 min-1) in the degradation of tetracycline (TC) in anoxic water environment was much higher than that of Fe-BC and Cu-BC; the effective degradation rate reached 85%. It was worth noting that the negative effects of Ca2+, Mg2+, and H2PO4- on TC degradation at ionic strengths greater than 15 mg/L were due to competition for active sites. Good stability and reusability were demonstrated in five consecutive cycle tests for low leaching of iron and copper. Combined with free radical quenching experiments and XPS analyses, the degradation of TC under air conditions was only 62%, with hydroxyl radicals (·OH) playing a dominant role. The synergistic interaction between Fe2+/Fe3+ and Cu0/Cu+/Cu2+ under nitrogen atmosphere enhances the redox cycling process; π-π adsorption, electron transfer processes, and active [H] were crucial for the degradation of TC; and possible degradation pathways of TC were deduced by LC-MS, which identified seven major aromatic degradation by-products. This study will provide new ideas and materials for the treatment of TC.

Novel prognostic marker TGFBI affects the migration and invasion function of ovarian cancer cells and activates the integrin αvß3-PI3K-Akt signaling pathway.

BACKGROUND: Individual patients with ovarian cancer show remarkably different prognosis. Present prognostic models for ovarian cancer mainly focus on clinico-pathological parameters, so quantifiable prognostic markers at molecular level are urgently needed. Platelets contribute to ovarian cancer progression, but have not been considered as biomarkers likely due to their instability. Here, we aimed to search for a stable prognostic marker from platelet-treated ovarian cancer cells, and explore its functions and mechanisms. METHODS: Microarrays analysis was done with platelet-treated SKOV-3 ovarian cancer cells. Relevant studies were searched in the Gene Expression Omnibus (GEO) database. The candidate genes were determined by differentially expressed genes (DEGs), Venn diagram drawing, protein-protein interaction (PPI) network, Cox proportional hazards model and Kaplan-Meier analysis. The expression of TGFBI in clinical samples was assessed by immunehistochemical staining (IHC), and the association of TGFBI levels with the clinic-pathological characteristics and prognosis in ovarian cancer patients was evaluated by univariate and multivariate analysis. The functions of TGFBI were predicted using data from TCGA, and validated by in vitro and in vivo experiments. The mechanism exploration was performed based on proteomic analysis, molecular docking and intervention study. RESULTS: TGFBI was significantly higher expressed in the platelet-treated ovarian cancer cells. An analysis of bioinformatics data revealed that increased expression of TGFBI led to significant decrease of overall survival (OS), progression-free survival (PFS) and post-progression survival (PPS) in ovarian cancer patients. Tissue microarray results showed that TGFBI was an independent factor for ovarian cancer, and TGFBI expression predict poor prognosis. Functionally, TGFBI affected the migration and invasion of ovarian cancer cells by regulation of epithelial mesenchymal transition (EMT) markers (CDH1 and CDH2) and extracellular matrix (ECM) degradation proteins (MMP-2). Mechanistically, TGFBI phosphorylated PI3K and Akt by combining integrin αvß3. CONCLUSIONS: We found out TGFBI as a novel prognostic indicator for ovarian cancer patients. TGFBI could promote metastasis in ovarian cancer by EMT induction and ECM remodeling, which might be associated with the activation of integrin αvß3-PI3K-Akt signaling pathway.

The emerging role of neutrophil extracellular traps in ulcerative colitis.

Ulcerative colitis (UC) is characterized by chronic non-recessive inflammation of the intestinal mucosa involving both innate and adaptive immune responses. Currently, new targeted therapies are urgently needed for UC, and neutrophil extracellular traps (NETs) are new therapeutic options. NETs are DNA-based networks released from neutrophils into the extracellular space after stimulation, in which a variety of granule proteins, proteolytic enzymes, antibacterial peptides, histones, and other network structures are embedded. With the deepening of the studies on NETs, their regulatory role in the development of autoimmune and autoinflammatory diseases has received extensive attention in recent years. Increasing evidence indicates that excess NETs exacerbate the inflammatory response in UC, disrupting the structure and function of the intestinal mucosal barrier and increasing the risk of thrombosis. Although NETs are usually assigned a deleterious role in promoting the pathological process of UC, they also appear to have a protective role in some models. Despite such progress, comprehensive reviews describing the therapeutic promise of NETs in UC remain limited. In this review, we discuss the latest evidence for the formation and degradation of NETs, focusing on their double-edged role in UC. Finally, the potential implications of NETs as therapeutic targets for UC will be discussed. This review aims to provide novel insights into the pathogenesis and therapeutic options for UC.

Diet-derived circulating antioxidants and risk of inflammatory bowel disease: a Mendelian randomization study and meta-analysis.

Background: Previous studies have shown conflicting results regarding the impact of circulating antioxidants on the risk of inflammatory bowel disease (IBD). In this study, our intent was to investigate the causal relationship between circulating antioxidants and IBD using Mendelian randomization (MR). Methods: Instrumental variables for absolute circulating antioxidants (ascorbate, retinol, lycopene, and ß-carotene) and circulating antioxidant metabolites (α-tocopherol, γ-tocopherol, ascorbate, and retinol) were screened from published studies. We obtained outcome data from two genome-wide association study (GWAS) databases, including the international inflammatory bowel disease genetics consortium (IIBDGC, 14,927 controls and 5,956 cases for Crohn's disease (CD), 20,464 controls and 6,968 cases for ulcerative colitis (UC), and 21,770 controls and 12,882 cases for IBD) and the FinnGen study (375,445 controls and 1,665 cases for CD, 371,530 controls and 5,034 cases for UC, and 369,652 controls and 7,625 cases for IBD). MR analysis was performed in each of the two databases and those results were pooled using meta-analysis to assess the overall effect of exposure on each phenotype. In order to confirm the strength of the findings, we additionally conducted a replication analysis using the UK Biobank. Results: In the meta-analysis of the IIBDGC and FinnGen, we found that each unit increase in absolute circulating level of retinol was associated with a 72% reduction in the risk of UC (OR: 0.28, 95% CI: 0.10 to 0.78, P=0.015). The UC GWAS data from the UK Biobank also confirmed this causal relationship (OR: 0.99, 95% CI: 0.97 to 1.00, P=0.016). In addition, there was suggestive evidence that absolute retinol level was negatively associated with IBD (OR: 0.41, 95% CI: 0.18 to 0.92, P=0.031). No other causal relationship was found. Conclusion: Our results provide strong evidence that the absolute circulating level of retinol is associated with a reduction in the risk of UC. Further MR studies with more instrumental variables on circulating antioxidants, especially absolute circulating antioxidants, are needed to confirm our results.

Autophagy: A potential target for natural products in the treatment of ulcerative colitis.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease primarily affecting the mucosa of the colon and rectum. UC is characterized by recurrent episodes, often necessitating lifelong medication use, imposing a significant burden on patients. Current conventional and advanced treatments for UC have the disadvantages of insufficient efficiency, susceptibility to drug resistance, and notable adverse effects. Therefore, developing effective and safe drugs has become an urgent need. Autophagy is an intracellular degradation process that plays an important role in intestinal homeostasis. Emerging evidence suggests that aberrant autophagy is involved in the development of UC, and modulating autophagy can effectively alleviate experimental colitis. A growing number of studies have established that autophagy can interplay with endoplasmic reticulum stress, gut microbiota, apoptosis, and the NLRP3 inflammasome, all of which contribute to the pathogenesis of UC. In addition, a variety of intestinal epithelial cells, including absorptive cells, goblet cells, and Paneth cells, as well as other cell types like neutrophils, antigen-presenting cells, and stem cells in the gut, mediate the development of UC through autophagy. To date, many studies have found that natural products hold the potential to exert therapeutic effects on UC by regulating autophagy. This review focuses on the possible effects and pharmacological mechanisms of natural products to alleviate UC with autophagy as a potential target in recent years, aiming to provide a basis for new drug development.

Ferroptosis in ulcerative colitis: Potential mechanisms and promising therapeutic targets.

Ulcerative colitis (UC) is a complex immune-mediated chronic inflammatory bowel disease. It is mainly characterized by diffuse inflammation of the colonic and rectal mucosa with barrier function impairment. Identifying new biomarkers for the development of more effective UC therapies remains a pressing task for current research. Ferroptosis is a newly identified form of regulated cell death characterized by iron-dependent lipid peroxidation. As research deepens, ferroptosis has been demonstrated to be involved in the pathological processes of numerous diseases. A growing body of evidence suggests that the pathogenesis of UC is associated with ferroptosis, and the regulation of ferroptosis provides new opportunities for UC treatment. However, the specific mechanisms by which ferroptosis participates in the development of UC remain to be more fully and thoroughly investigated. Therefore, in this review, we focus on the research advances in the mechanism of ferroptosis in recent years and describe the potential role of ferroptosis in the pathogenesis of UC. In addition, we explore the underlying role of the crosslinked pathway between ferroptosis and other mechanisms such as macrophages, neutrophils, autophagy, endoplasmic reticulum stress, and gut microbiota in UC. Finally, we also summarize the potential compounds that may act as ferroptosis inhibitors in UC in the future.