In this paper, we report the construction of chiral ferrocene-containing (Fc) supramolecular platforms with high symmetry and well-defined geometry via dynamic covalent chemistry. Starting from amino acid hydrazides and ferrocene aldehydes, we obtained respective Fc-acylhydrazones with well-defined conformations, that display intense circular dichroism (CD) signals in the visible region associated with ferrocene-centered electronic transitions. CD and UV-vis spectroscopy, supported by computational analysis, reveal efficient transfer of chirality from the remote stereogenic centers to the Fc unit and a correlation between amino acid configuration, Fc helicity, and CD sign (l-amino acid → (P)-Fc → (-)CD at 470 nm). Exploiting the dynamic character of the acylhydrazone linker, amino acid trihydrazide l-2 was further assembled with ferrocene dialdehyde into D3-symmetric double-decker trigonal platform Fc3(l-2)2 with high synthetic efficiency (>90%). Under these conditions, narcissistic chiral self-sorting occurs via dynamic covalent exchange, which results in the formation of homochiral platforms from racemic precursors. The combination of conformationally locked axial chirality, reversible covalent connectivity, and inherent redox activity establishes new amino acid-based motifs as promising modules for constructing chiral Fc-containing porous architectures such as molecular cages, MOFs, and COFs, with potential for asymmetric electrochemical applications.
Diaryl ureas and thioureas have long been known to uncouple oxidative phosphorylation in isolated mitochondria and cells. However, the mechanism of this action remains poorly understood. The prevailing current view is that substituted diaryl ureas can increase the proton conductance of lipid membranes by forming complexes with fatty acids. For 1,3-bis[4-(trifluoromethyl)phenyl]urea (TFMP-urea), we showed that this substituted diphenylurea, in the absence of fatty acids at neutral pH, accelerated proton transport and H+/Cl- symport on planar bilayer lipid membranes (BLMs) and liposomes loaded with the fluorescent pH-sensitive probe 8-hydroxypyrene-1,3,6-trisulfonic acid. The protonophoric action of TFMP-urea proceeded via translocation of neutral protonated form and anionic deprotonated form through the membrane. The presence of palmitic acid in the lipid mixture led to a several-fold increase in the BLM current mediated by TFMP-urea and an improvement in its proton selectivity. We also showed that bovine serum albumin reduced the BLM current mediated by TFMP-urea due to its ability to bind this compound.
Nanotechnology-enabled NPK fertilization combined with biostimulants offers a sustainable approach to enhance crop productivity, resource-use efficiency, and environmental performance in specialty crops. A two-year (2022-2023) factorial experiment (3 × 2), arranged in a completely randomized design, evaluated the interactive effects of nano humic acid-silicic acid-based Triple 20 NPK fertilizers (nano-NPK) applied at 40, 80, and 120 kg ha ⁻ ¹, with and without 0.3% salicylic acid (SA) as biostimulant, on processing tomato (Solanum lycopersicum L. cv. BHN 685) grown in a low-fertility soil under drip-irrigated, raised bed plasticulture. Conventional Triple 20 NPK fertilization at 120 kg ha ⁻ ¹ served as the control. Multivariate statistical analyses demonstrated that nano-NPK fertilization and SA, alone or in combination, significantly improved tomato yield components, water use efficiency (WUE), and fertilizer use efficiency (FUE), while reducing cull fruit and increasing marketable yield. Among treatments, 80 kg ha ⁻ ¹ nano-NPK combined with 0.3% SA produced both total and marketable yields equivalent to or exceeding those obtained with 120 kg ha ⁻ ¹ nano-NPK or conventional fertilization, alongside higher nutrient, and water utilization. These improvements were associated with enhanced nutrient bioavailability, uptake, and photosynthetic performance due to nano-enabled NPK fertilization, with SA further promoting plant growth and fruit quality. This combination reduced fertilizer input by up to 33% without compromising yield, achieving WUE and FUE comparable to or better than conventional NPK fertilization (120 kg ha-1). Economically, 80 kg ha ⁻ ¹ nano-NPK + 0.3% SA achieved the highest benefit-cost ratio (1.26) and net return (US $1,988 ha ⁻ ¹), outperforming conventional NPK fertilization. Environmental assessment indicated improved energy use efficiency (4-6%) and lower greenhouse gas (GHG) intensity per unit of marketable yield. Although total GHG emissions were statistically similar at higher application rates, nano-NPK, SA, or their combination reduced GHG intensity, highlighting their sustainability advantage. Overall, integrating 80 kg ha ⁻ ¹ nano-NPK with 0.3% SA optimizes yield, profitability, and environmental stewardship, offering an efficient pathway for sustainable intensification of tomato production.
Electrocatalytic reduction of CO2 to CH4 is a promising strategy for converting renewable energy into a desirable high-energy-density fuel with significant compatibility with the existing natural gas infrastructure. However, conventional alkaline and neutral CO2-to-CH4 systems exhibit low carbon utilization due to the loss of CO2 into (bi)carbonate. Conducting CO2 electroreduction in acid can alleviate carbonation issues but suffers from moderate CH4 selectivity owing to competing hydrogen evolution. Herein, we report that thiocyanate (SCN-), a well-known poison in electrocatalysis, can remarkably enhance acidic electrocatalytic CO2-to-CH4 performance, specifically resulting in a record-high CH4 Faradaic efficiency of 81.8% (accompanied by a CH4 partial current density of 213.3 mA cm-2) and a single-pass carbon efficiency of 65.2% when using a CeO2-supported Cu single-atom material as the model catalyst. We demonstrate that SCN- enables the coordination with Cu single sites, forming the SCN--stabilized Cu(I) species, which effectively suppresses the competing hydrogen evolution reaction and, more importantly, manipulates the binding of *CHO to promote its protonation to *CHOH, thereby leading to selective and efficient CH4 production. This work highlights the unique role of thiocyanate in promoting the selective reduction of CO2 to CH4 and offers insights into the design of surface chemistry for precise regulation of catalytic processes to achieve targeted product production.
Ethanol extracts from four species of green algae were comparatively evaluated for anti-melanogenic activity using B16F10 mouse melanoma cells. The extract derived from Ulva prolifera demonstrated the strongest inhibitory effect on melanin synthesis and was thus selected for further investigation to isolate and identify its bioactive constituents. Through sequential chromatographic techniques, two active compounds-1-hexadecatetraenoylglycerol and 1-hexadecatetraenoyl-3-β-D-galactopyranosylglycerol-were isolated and structurally characterized via NMR and mass spectrometric analyses. Notably, hexadecatetraenoic acid alone did not exhibit anti-melanogenic activity under the same experimental conditions, whereas its glycerol-conjugated form, 1-hexadecatetraenoylglycerol, significantly suppressed melanin production. Additionally, neither the ethanol extract of U. prolifera nor the isolated compounds directly inhibited tyrosinase activity, suggesting that they may influence melanogenesis through indirect mechanisms. These results suggest that the molecular configuration of fatty acids plays an important role in anti-melanogenic activity and highlight the potential of lipid components from U. prolifera as functional anti-melanogenic agents.
Efficient electrocatalytic water splitting demands precise hetero-interface engineering. This work synthesizes Pd-anchored MoO2@carbon hollow nanospheres (Pd/MoO2@C HNSs) via a facile one-step polymerization, leveraging automatic Pd-O-Mo bonding to immobilize Pd nanoparticles on MoO2 nanoclusters. X-ray absorption near-edge structure (XANES) analysis confirms enhanced electron transfer from Pd to oxygen, enabling exceptional acidic hydrogen evolution reaction (HER) performance: an ultralow overpotential of 28 mV at 10 mA cm-2, a mass activity of 4.82 A mg-1 (34-fold higher than Pt/C), and a turnover frequency of 2.53 s-1 (18-fold higher than Pt20%/C). The Pd integration effectively compensates the intrinsic low active-sites density on MoO2 while accelerating H2 desorption and HER kinetics. Assembled into an asymmetric-electrolyte electrolyzer harvesting electrochemical neutralization energy (ΔG = 0.83 eV), this system achieves hydrogen production at 10 mA cm-2 with only 0.63 V applied voltage. This work highlights hetero-interface modulation as a universal strategy to activate inert electrocatalysts for sustainable energy conversion.
Tranexamic acid (TXA) reduces perioperative blood loss, but comparative effectiveness and safety across administration routes remain uncertain. We evaluated topical, intravenous [IV], and oral TXA in unilateral total hip and knee arthroplasty. Using Taiwan's national health insurance database (2012-2021), we identified patients undergoing unilateral arthroplasty and evaluated perioperative TXA use, red blood cell transfusion, and adverse events within 60 days after discharge. Conditional logistic regression and six propensity-score-matched comparisons were conducted: topical vs none, IV vs none, oral vs none, topical vs IV, topical+ 1.0g IV vs topical alone, and IV+ 1.0g topical vs IV alone. Compared with no TXA, all routes were associated with lower transfusion risk (topical: RR 0.45, 95%CI 0.41-0.48, p <0.001; IV: RR 0.80, 95%CI 0.79-0.84, p <0.001; oral: RR 0.82, 95%CI0.73-0.92, p=0.007). Topical and IV TXA were associated with similar risk (RR 1.09, 95%CI:0.96-1.24, p>0.999), and the combined use was not associated with a different risk compared with either route alone. Topical TXA was associated with the greatest reduction in predicted transfusion risk at low dose (- 3,087 per 10,000 [-2,886, -3,276], 0→3.0g). Overall, TXA use was not associated with increased venous thromboembolism (VTE), infections, or wound complications. A higher VTE incidence was observed with topical TXA in patients with prior vascular disease without pharmacological prophylaxis, but this was not significant after adjustment for confounders. TXA was not associated with renal injury overall, but high-dose IV (>3.0 g) or oral (>8.0 g) TXA increased predicted risk (~10%) in patients with preexisting renal disease. TXA use was associated with substantial transfusion reduction without an overall increase in adverse events. No administration route or combination proved superior. Caution is warranted with higher-dose IV or oral TXA in patients with renal disease, and the association between topical TXA and VTE in high-risk patients merits further investigation.
Pancreatic cancer is a highly lethal malignancy that is frequently accompanied by drug resistance. Betulinic acid (BA) has therapeutic potential; its clinical utility is hampered by poor solubility and a lack of organelle-specific targeting. Given the functional abnormalities of tumor mitochondria, mitochondria-targeted interventions may enhance therapeutic efficacy while reducing systemic toxicity. Using BA as the parent scaffold, we designed and synthesized 30 mitochondria-targeted BA derivatives by attaching delocalized lipophilic cations (DLCs), including triphenylphosphonium (TPP+), at the C-28 position. We performed in vitro activity screening, transcriptomic analysis, mechanistic validation, and in vivo efficacy and safety assessments. Compound 14 showed the strongest cytotoxicity against PANC-1 cells (IC50 = 1.36 ± 0.09 μM), which was markedly superior to BA (IC50 = 79.29 ± 6.87 μM) with a fold reduction of approximately 58. Transcriptomics and mechanistic analysis indicate that compound 14 accumulated in mitochondria, inducing excessive ROS production, which then led to the collapse of mitochondrial membrane potential (ΔΨm) and mitochondrial dysfunction. This mitochondrial dysfunction subsequently promoted cytochrome c release and activated the caspase cascade, thereby triggering intrinsic mitochondrial apoptosis. Concurrently, compound 14 induced ferroptosis by upregulating ACSL4 and downregulating GPX4, which was accompanied by increased lipid peroxidation products and intracellular Fe2+. The ROS scavenger N-acetylcysteine significantly reversed these ferroptosis-associated changes. In vivo, compound 14 significantly inhibited tumor growth in xenografts without evident systemic toxicity. Compound 14, a mitochondria-targeted BA derivative, inhibits pancreatic cancer via ROS-driven mitochondrial apoptosis and ferroptosis, showing favorable efficacy and safety and potential for preclinical development.
The PhI(OAc)2-oxidation of the triterpene lupeol by manganese porphyrin was achieved, leading to 94% of lupeol conversion. Conditions aligned with principles of green chemistry, including the use of ethyl acetate as a solvent and iodobenzene diacetate as an oxidant, were studied. This approach led to the production of eight products from lupeol, notably achieving transformations at the C20 olefin moiety; six lupeol's products were isolated whereas the other two had their structures proposed supported on basic chemical tests (e.g., Fehling's test) and well‑established reactivity patterns in organic chemistry. These modifications were performed without the typical preceding protection of the C3 hydroxyl of lupeol, simplifying the synthetic route. Besides, the isopropenyl group of lupeol was converted to carboxylic acids through one-pot oxidation. This study reinforces the promising use of manganese porphyrins as catalysts for the oxidative transformation of other natural products of biological interest.
An innovative and green anodic "suspension electrolysis" strategy is designed for lithium extraction from industrial spent LiCoO2 "black powders", without additional acid, base or oxidizing/reducing agents required. As thoroughly illustrated by the electrolytic mechanism, Li ions driven by the electric energy are leached into the electrolyte while lithium-deficient LixCoO2 can be acquired as the anodic residual powders. The electrolysis process achieves an outstanding Li leaching efficiency of 92.1% and the Li ions can be recycled in the form of Li2CO3 through a precipitate reaction by Na2CO3. The post-produced cobalt oxide and Li2CO3 can be subjected to a solid-phase heat treatment for the regeneration of layered LCO. The regenerated LCO exhibits a discharge specific capacity of 149 mAh/g at 0.5 C, covering around 98.4% of the commercial LCO, and the capacity retention rate reaches up to 91.6% after 200 cycles at 0.5 C. This work provides an eco-friendly and scalable solution for recycling and regenerating spent LCO cathode materials.
Osteosarcoma is a severe bone malignancy, and current chemotherapeutic strategies often struggle to effectively halt disease progression. Galbanic acid (GBA) and auraptene (AUR) are natural sesquiterpene coumarins known for their diverse pharmacological activities. This study is the first to evaluate the ability of GBA and AUR to enhance Alkeran-induced toxicity in osteosarcoma cells. GBA and AUR were isolated from Ferula szowitsiana, and the viability and apoptosis of osteosarcoma cells were assessed following treatments with GBA, AUR, and Alkeran-alone and in combination. An efflux assay was conducted to determine the functional interactions of AUR and GBA with ABC transporters, and molecular docking and dynamics simulations were performed to explore their potential interactions. Single treatment of cells with each agent did not induce significant toxicity: however, combination treatments of GBA or AUR with Alkeran significantly (p < 0.0001) reduced cell viability. Synergistic interaction was strong for both coumarins and Alkeran, supported by flow cytometry detection of apoptosis and ABC transporter activity. Molecular docking and dynamics simulations demonstrated favorable and stable interactions of coumarins with ABC transporters. In conclusion, this study provides strong support that GBA and AUR enhanced Alkeran efficacy in osteosarcoma cells by targeting ABC transporters.
Lipedema is a chronic, progressive disorder of subcutaneous adipose tissue that mainly affects women. It is characterized by disproportionate fat hypertrophy, pain, bruising, and marked resistance to diet and exercise. Tumescent liposuction remains the only effective treatment to slow or reverse disease progression, but involves large volumes and fragile microvasculature, increasing bleeding risk. This study aimed to evaluate whether perioperative tranexamic acid (TXA) reduces intraoperative blood loss, postoperative bruising, and early complications in lipedema liposuction. We retrospectively analyzed 230 staged liposuction procedures for lipedema performed between 2021 and 2024 at a single center. Patients received TXA intravenously, locally, or in combination, or no TXA. Primary outcomes were estimated intraoperative blood loss and postoperative ecchymosis. Secondary endpoints included hematoma, transfusion need, thromboembolic events, infections, and recovery time. All TXA groups showed significantly lower intraoperative blood loss and hemoglobin drop versus controls (p < 0.01). Local and combined routes were most effective, with the combined approach yielding the lowest ecchymosis scores. Hematoma rates dropped from 12% (no TXA) to 0-6.7% (TXA), and no thromboembolic or infectious complications were observed. No TXA-treated patients required transfusions, while 6% of controls did. TXA use in lipedema liposuction significantly reduces bleeding and bruising without increasing thromboembolic risk. Combined systemic and local administration appears most beneficial. These findings support TXA as a safe, effective adjunct in multistage, high-volume liposuction for lipedema. Prospective trials are needed to confirm the optimal protocol in this unique population. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .
Industrial production of malic acid remains dependent on fossil resources or, when performed microbiologically, on sugar-based feedstocks. Both routes come with caveats, generating emissions and competing with food supply. The use of CO₂-derived one-carbon substrates offers a promising alternative to circumvent these constraints. In this study, the malic acid production process from methanol in metabolically engineered Ogataea polymorpha NYCY495 LEU-ΔSTE12 Pyc Mdh MAE1 strain was optimised and scaled up. A two-phase cultivation strategy, using glycerol for biomass formation and methanol for product synthesis, was established in shake flasks and subsequently transferred to a 1 L bioreactor. Process optimisation through automated feeding strategies was evaluated. DO-based feeding was the most effective approach, using a combination of methanol and glycerol, achieving a final molar yield of 0.1 molMA molMeOH ⁻¹ and a maximum productivity of 0.5 g L⁻¹ h⁻¹. This successful fermentation strategy was validated using green methanol, showcasing the feasibility of "closing the loop" as envisioned in the bioeconomy. Finally, a comparative study of the effect of glycerol, methanol, and their mixture on O. polymorpha NYCY495 LEU-ΔSTE12 Pyc Mdh MAE1 methanol metabolism, peroxisome biogenesis, and cellular redox balance is presented, supporting the positive cumulative effect of both on gene transcription.
To address challenges in fruit preservation, a sprayable hydrogel with aggregation-induced emission (AIE) activity was developed through the self-assembly of glycyrrhizic acid (GA) and berberine (BBR). Its formation mechanism and microstructure were elucidated by rheology, microscopy, spectroscopy, and molecular dynamics simulation. The hydrogel exhibited antioxidant activity via a stimulus-responsive release behavior, in which GA dominated under hydrophobic conditions, while the gradual release of BBR enhanced efficacy under hydrophilic conditions. Sustained antimicrobial performance was also achieved, prolonging the activity of free BBR over 12-24 h. Against Rhizopus stolonifer, the hydrogel maintained an inhibition rate of about 70% after 65 h, whereas free BBR decreased to below 10%. Integrating near-infrared spectroscopy (NIR), electronic nose (E-nose), and headspace solid-phase microextraction gas chromatography-mass spectrometry (HS-SPME-GC-MS) analyses further demonstrated that the hydrogel effectively preserved key fresh flavor compounds in strawberries, highlighting its potential as an eco-friendly and multifunctional preservation system.
Raw goat milk was explored as a source of lactic acid bacteria (LAB) with potential probiotic properties. Following 16S rRNA gene sequencing, Lactiplantibacillus plantarum PP101-STR and Lactococcus lactis PP104-STR were selected for further probiotic assessment. L. plantarum PP101-STR exhibited broad antagonistic activity against both Gram-positive and Gram-negative pathogens, especially Salmonella enterica ATCC 13312 and maintained high viability (> 83%) under simulated gastric conditions (pH 2.0-3.0) and bile salt exposure. This strain also demonstrated high cell surface hydrophobicity, along with strong auto-aggregation and co-aggregation capacities, which were associated with significantly enhanced adhesion to Caco-2 and HT-29 cell lines and effective competitive exclusion of pathogenic bacteria (p≤0.05). In addition, L. plantarum PP101-STR displayed strong antioxidant activity, as determined by total phenolic content, FRAP, DPPH, and ABTS assays, exceeding that of L. lactis PP104-STR. Its cell-free supernatant (CFS) exhibited notable α-glucosidase and α-amylase inhibitory activities, indicating potential for glucose regulation. Antiproliferative evaluation revealed that L. plantarum PP101-STR markedly suppressed colorectal cancer cell growth in a dose-dependent manner. Importantly, low lactate dehydrogenase release (8.11-8.86%) and maintained viability in MRC-5 cells indicated minimal membrane damage and low cytotoxicity toward normal cells, supporting a non-lytic mechanism potentially involving apoptosis-related pathways. On the basis of the present finding, L. plantarum PP101-STR demonstrates strong probiotic potential and multiple biologically relevant activities in vitro, supporting its further investigation in applications related to intestinal health.
The co-dependent challenges of environmental remediation and solar energy conversion necessitate the development of highly efficient, noble-metal-free photocatalytic systems, particularly those engineered to overcome rapid charge recombination while preserving high redox potential. Herein, we report the construction of an intimate PTA/Ni3V2O8 (Phosphotungstic Acid/Nickel Vanadate) nanocomposite via a facile hydrothermal method, aiming to leverage the multi-electron redox properties of PTA as a highly efficient charge mediator. Structural and optical characterization confirmed the formation of a robust heterojunction with enhanced visible-light harvesting capabilities. Under simulated solar irradiation, the optimized PTA10/Ni3V2O8 composite demonstrated remarkable dual-functional performance: achieving 94.4% degradation of Methylene Blue (MB) with a kinetic rate constant ~ 7.2-fold higher than that of pristine Ni3V2O8. Furthermore, the composite exhibited superior CO2 photoreduction activity, doubling the yield of valuable liquid fuels (HCOOH and HCHO) in 6 h. Detailed mechanistic analyses, encompassing photoluminescence (PL) spectroscopy and radical trapping experiments, validated the direct Z-scheme charge transfer mechanism. This pathway successfully spatialized charge carriers, confirmed by PL quenching, and preserved their potency, evidenced by the prevalence of highly oxidizing holes (h+ on the PTA HOMO) and potent reducing species (•O2- derived from the Ni3V2O8 CB). This work establishes PTA as an effective interfacial promoter for vanadate-based materials, presenting a sustainable, high-performance Z-scheme composite for advanced environmental and energy applications.
Squamous cell carcinoma in situ (isSCC) is an early-stage cutaneous malignancy that requires effective treatment to prevent progression to invasive SCC. Aminolevulinic acid photodynamic therapy (ALA-PDT) is a noninvasive treatment that selectively targets neoplastic cells. This study evaluated the effectiveness, safety, and tolerability of ALA-PDT for the treatment of patients with facial isSCC. In this single-center, investigator-initiated, open-label study (NCT06159842), adult patients with biopsy-confirmed facial isSCC received 2 treatments with 20% ALA and blue light exposure, administered 28 days (± 3 days) apart. Lesions were excised for histopathological assessment 8 weeks after the second treatment. The primary endpoint was complete histological clearance at the end of treatment (EOT). Secondary outcomes included clinical clearance and tolerability. A total of 32 patients were enrolled in this study, of whom 30 completed the study. All patients achieved complete histological clearance at EOT. Clinical clearance was observed in all patients prior to excision, with 40% achieving clearance by day 49 and the remainder by day 69. Local skin reactions, including erythema and flaking, were mild and resolved over time. Only 1 patient experienced temporary hyperpigmentation. Pain scores remained low (mean, 2.71/10). Two patients reported adverse events considered unrelated to treatment. ALA-PDT achieved 100% complete histological and clinical clearance with minimal adverse effects, demonstrating its potential as a safe, effective, and cosmetically favorable alternative to surgical excision for the treatment of facial isSCC. Further studies are needed to assess long-term recurrence rates and broader applications.
The global rise in pet ownership has increased demand for health-promoting products, particularly probiotics designed to support gastrointestinal and immune health in companion animals. However, most commercial products rely on non-host-adapted strains, which may limit gastrointestinal colonization and host-specific benefits. To address this gap, 56 bacterial isolates were obtained from the fecal and milk microbiota of clinically healthy dogs and cats. Among these, Limosilactobacillus reuteri DF/KS2, derived from the fecal microbiota of a Kangal Shepherd dog, and Enterococcus faecium CM/BS2 derived from the milk microbiota British Shorthair cat, were selected based on their broad-spectrum antimicrobial activity. Both strains exhibited a safe profile, as evidenced by γ-hemolysis and susceptibility to a panel of clinically relevant antibiotics. Under simulated gastrointestinal conditions, CM/BS2 and DF/KS2 tolerated highly acidic environments and demonstrated resilience against digestive enzymes and bile salts. Furthermore, both isolates displayed strong auto-aggregation and co-aggregation abilities with key pathogens, while adhesion assays using Caco-2 cells confirmed their capacity to inhibit pathogen attachment. Immunomodulatory evaluations further revealed that both strains effectively reduced pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) and enhanced anti-inflammatory IL-10 production in canine and feline macrophages. Optimal growth occurred at 37 °C after 24 h in 2% molasses medium, and shelf-life studies demonstrated that freeze-dried cultures retained high viability over six months at - 20 °C. Collectively, these findings highlight the probiotic potential of host-adapted L. reuteri DF/KS2 and E. faecium CM/BS2, emphasizing their suitability for inclusion in species-specific probiotic formulations aimed at supporting gastrointestinal and immune health in dogs and cats.
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Chronic intermittent hypoxia (CIH), a hallmark pathological feature of obstructive sleep apnea (OSA), is extensively linked to hepatic steatosis in high-fat-diet-induced mice. However, the association between CIH and hepatic steatosis in lean mice, as well as the potential involvement of gut microbiota-related mechanisms, remains poorly understood. Four hundred participants in the Shanghai Sleep Health Study were included to assess the association between apnea-hypopnea index (AHI) and hepatic steatosis index (HSI). To characterize CIH-associated phenotypes and explore microbiota-related alterations in lean mice, liver histology, inflammatory cytokine profiling, metagenomic sequencing with antibiotic intervention, plasma untargeted metabolomics, and liver transcriptomics were performed. As a result, AHI was positively associated with HSI in non-obese participants. In lean mice, 16-week CIH alone induced hepatic steatosis and inflammation, accompanied by significant alterations in gut microbiota composition. Antibiotic treatment attenuated hepatic steatosis and inflammation in 16-week CIH-exposed mice. Metagenomic analysis revealed CIH-associated depletion of Bacteroides uniformis, which was reversed by antibiotic treatment. Plasma metabolomic profiling identified deoxycholic acid as a metabolite exhibiting opposite, phenotype-aligned alterations between CIH and CIH plus antibiotic groups and showing the strongest correlation with Bacteroides uniformis abundance. In parallel, liver transcriptomics revealed coordinated alterations in bile acid-related metabolic pathways and PPAR signaling consistent with CIH-induced and antibiotic-sensitive metabolic remodeling. Together, these findings indicate that prolonged CIH exposure induces hepatic lipid accumulation in lean mice and is associated with coordinated, antibiotic-sensitive alterations in gut microbiota composition, bile acid metabolism, and hepatic transcriptional programs, suggesting a potential involvement of gut microbiota-bile acid-liver interactions in CIH-associated hepatic steatosis.IMPORTANCEObstructive sleep apnea (OSA) is increasingly recognized as a contributor to metabolic dysfunction, yet its role in hepatic steatosis independent of obesity remains incompletely understood. This study shows that chronic intermittent hypoxia (CIH), a defining pathological feature of OSA, is sufficient to induce hepatic steatosis and inflammation in lean mice, independent of dietary manipulation. These findings broaden current understanding of OSA-associated liver disease beyond the context of obesity and metabolic syndrome. By integrating metagenomic sequencing, plasma metabolomics, and liver transcriptomics, this work highlights coordinated alterations in gut microbial composition, bile acid profiles, and hepatic lipid-related transcriptional programs associated with CIH exposure. Depletion of Bacteroides uniformis and elevation of deoxycholic acid were linked to CIH-induced hepatic phenotypes and were sensitive to antibiotic intervention, supporting a contributory role of gut microbiota-bile acid interactions in this process. Together, these findings underscore the potential importance of gut microbiota-host metabolic crosstalk in OSA-associated hepatic steatosis and suggest that microbiota- or bile acid-targeted strategies may warrant further investigation as adjunctive approaches for risk stratification and therapeutic intervention in OSA-related liver disease.