PLA plastic particles disrupt bile acid metabolism leading to hepatic inflammatory injury in male mice.

Microplastics, such as polylactic acid (PLA), are ubiquitous environmental pollutants with unclear implications for health impact. This study aims to elucidate the mechanisms of PLA-induced inflammatory liver injury, focusing on disturbance of bile acid metabolism. The in vitro PLA exposure experiment was conducted using HepG2 cells to assess cell viability, cytokine secretion, and effects on bile acid metabolism. In vivo, male C57BL/6 J mice were exposed to PLA for ten days continuously, liver function and histopathological assessment were evaluated after the mice sacrificed. Molecular analyses including quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blotting, were applied to evaluate the expression of bile acid metabolizing enzymes and transporters. PLA exposure resulted in decreased cell viability in HepG2 cells, increased inflammation and altered bile acid metabolism. In mice, PLA exposure resulted in decreased body weight and food intake, impaired liver function, increased hepatic inflammation, altered bile acid profiles, and dysregulated expression of bile acid metabolic pathways. PLA exposure disrupts bile acid metabolism through inhibition of the CYP7A1 enzyme and activation of the FGF-JNK/ERK signaling pathway, contributing to liver injury. These findings highlight the potential hepatotoxic effects of environmentally friendly plastics PLA and underscore the need for further research on their biological impact.

High-Entropy Metal Nitride Embedded in Concave Porous Carbon Enabling Polysulfide Conversion in Lithium-Sulfur Batteries.

The practical implementation of lithium-sulfur batteries is severely hindered by the rapid capacity fading due to the solubility of the intermediate lithium polysulfides (LiPSs) and the sluggish redox kinetics. Herein, high-entropy metal nitride nanocrystals (HEMN) embedded within nitrogen-doped concave porous carbon (N-CPC) polyhedra are rationally designed as a sulfur host via a facile zeolitic imidazolate framework (ZIF)-driven adsorption-nitridation process toward this challenge. The configuration of high-entropy with incorporated metal manganese (Mn) and chromium (Cr) will optimize the d-band center of active sites with more electrons occupied in antibonding orbitals, thus promoting the adsorption and catalytic conversion of LiPSs. While the concave porous carbon not only accommodates the volume change upon the cycling processes but also physically confines and exposes active sites for accelerated sulfur redox reactions. As a result, the resultant HEMN/N-CPC composites-based sulfur cathode can deliver a high specific capacity of 1274 mAh g-1 at 0.2 C and a low capacity decay rate of 0.044% after 1000 cycles at 1 C. Moreover, upon sulfur loading of 5.0 mg cm-2, the areal capacity of 5.0 mAh cm-2 can still be achieved. The present work may provide a new avenue for the design of high-performance cathodes in Li-S batteries.

Toward High-Performance Mg/S Batteries with M4-Assisted Mg(AlCl4 )2 /PYR14TFSI/DME Electrolyte and MoS2 @CMK/S Cathode.

Rechargeable magnesium batteries (RMBs) are considered as one of the most promising candidates for next-generation batteries. However, the popularization of RMBs is seriously plagued due to the lack of suitable non-nucleophilic electrolytes and the passivation of Mg anode. Herein, a novel non-nucleophilic electrolyte is developed by introducing (s)-1-methoxy-2-propylamine (M4) into themagnesium aluminum chloride complex (MACC)-like electrolyte. The as-synthesizes Mg(AlCl4 )2 -IL-DME-M4 electrolyte enables robust reversible cycling of Mg plating/stripping with low overpotential, high anodic stability, and ionic conductivity (8.56 mS cm-1 ). These features should be mainly attributed to the in situ formation of an MgF2 containing Mg2+ -conducting interphase, which dramatically suppresses the passivation and parasitic reaction of Mg anode with electrolyte. Remarkably, the Mg/S batteries assemble with as-synthesize electrolyte and a new type MoS2 @CMK/S cathode deliver unprecedented electrochemical performance. Specifically, the Mg/S battery exhibited the highest reversible capacity up to 1210 mAh g-1 at 0.1 C, excellent rate capability and satisfactory long-term cycling stability with a reversible capacity of 370 mAh g-1 (coulombic efficiency of ≈100%) at 1.0 C for 600 cycles. The study findings provide a novel strategy and inspiration for designing efficient non-nucleophilic Mg electrolyte and suitable sulfur-host materials for practical Mg/S battery applications.

Self-assembly of the imidazolium surfactant in aprotic ionic liquids. The anion effect of aprotic ionic liquids.

The structure of ionic liquids (ILs) has an influence on their physiochemical properties, determining their performance as self-assembly media. In this study, we focus on the anion effect of aprotic ionic liquids (AILs). The aggregation behaviours of the cationic surfactant 1-hexadecyl-3-methylimidazolium bromide (C16mimBr) have been investigated in the imidazolium AILs with the 1-ethyl-3-methyl imidazolium cation and different anions, including nitrate, ethylsulfate, bis(trifluoromethylsulfonyl) imide and tetrafluoroborate. Surface adsorption parameters of C16mimBr were determined using surface tension measurements, and the critical micellization concentration values in AILs vary for their different cohesive energy. The micellar and lamellar lyotropic liquid crystal phases emerge with the increase of C16mimBr concentrations. The structure and properties of aggregates were determined using small angle X-ray scattering, polarized optical microscopy, rheology and differential scanning calorimetry. The anion effects of AILs on the phase behaviours and structure and properties of aggregates were analysed and discussed. The lamellar lyotropic liquid crystals have shown good conductivity, as confirmed by electrochemical impedance spectroscopy characterization. Our results enhance the understanding of the structure effect of ILs as self-assembly media and contribute to the design of tailorable solvents.

The role of silver nanoparticles alone and combined with imipenem on carbapenem-resistant Klebsiella pneumoniae.

AIMS: Carbapenem-resistant Klebsiella pneumoniae (CRKP) infections poses a significant threat to human health, necessitating urgent development of new antimicrobial agents. Silver nanoparticles (AgNPs), which are among the most widely used engineered nanomaterials, have been extensively studied. However, the impact of AgNPs on CRKP and the potential for drug resistance development remain inadequately explored. METHODS AND RESULTS: In this study, broth dilution method was used to determine the minimum inhibitory concentration (MIC) was determined using the broth dilution method. Results indicated MIC values of 93.1 ± 193.3 µg ml-1 for AgNPs, 2.3 ± 5.1 µg ml-1 for AgNO3, and 25.1 ± 48.3 µg ml-1 for imipenem (IMI). The combined inhibitory effect of AgNPs and IMI on CRKP was assessed using the checkerboard method. Moreover, after 6-20 generations of continuous culture, the MIC value of AgNPs increased 2-fold. Compared to IMI, resistance of Kl. pneumoniae to AgNPs developed more slowly, with a higher fold increase in MIC observed after 20 generations. Whole-genome sequencing revealed four nonsynonymous single nucleotide polymorphism mutations in CRKP after 20 generations of AgNP treatment. CONCLUSION: We have demonstrated that AgNPs significantly inhibit CRKP isolates and enhance the antibacterial activity of imipenem against Kl. pneumoniae. Although the development of AgNP resistance is gradual, continued efforts are necessary for monitoring and studying the mechanisms of AgNP resistance.

Exploration of costunolide derivatives as potential anti-inflammatory agents for topical treatment of atopic dermatitis by inhibiting MAPK/NF-κB pathways.

Atopic dermatitis (AD) is a common inflammatory disease and it is very difficult to treat. In the present work, a series of costunolide derivatives have been prepared, and in vitro and in vivo anti-inflammatory activities have evaluated. The results showed that most derivatives displayed good inhibition of NO generation with low cytotoxicity, and 7d could inhibit the phosphorylation of P38, P65 NF-κB and IκB-α in LPS-induced RAW264.7 model. The in vivo researches showed that 7d could improve skin injury symptoms, decrease Th2-type cytokine levels, inhibit HIS levels, alleviate scratching and repaire the damaged skin barrier through the inhibition of phosphorylation of MAPK and NF-κB signaling pathways on MC903-induced AD model. Therefore, costunolide derivatives may be new potent anti-AD agents for further study.

Synthesis, structure-activity relationship and biological evaluation of indole derivatives as anti-Candida albicans agents.

In this work, we synthesized a series of indole derivatives to cope with the current increasing fungal infections caused by drug-resistant Candida albicans. All compounds were evaluated for antifungal activities against Candida albicans in vitro, and the structure-activity relationships (SARs) were analyzed. The results indicated that indole derivatives used either alone or in combination with fluconazole showed good activities against fluconazole-resistant Candida albicans. Further mechanisms studies demonstrated that compound 1 could inhibit yeast-to-hypha transition and biofilm formation of Candida albicans, increase the activity of the efflux pump, the damage of mitochondrial function, and the decrease of intracellular ATP content. In vivo studies, further proved the anti-Candida albicans activity of compound 1 by histological observation. Therefore, compound 1 could be considered as a novel antifungal agent.

Toward evaluation of multiresolution cortical thickness estimation with FreeSurfer, MaCRUISE, and BrainSuite.

Advances in Magnetic Resonance Imaging hardware and methodologies allow for promoting the cortical morphometry with submillimeter spatial resolution. In this paper, we generated 3D self-enhanced high-resolution (HR) MRI imaging, by adapting 1 deep learning architecture, and 3 standard pipelines, FreeSurfer, MaCRUISE, and BrainSuite, have been collectively employed to evaluate the cortical thickness. We systematically investigated the differences in cortical thickness estimation for MRI sequences at multiresolution homologously originated from the native image. It has been revealed that there systematically exhibited the preferences in determining both inner and outer cortical surfaces at higher resolution, yielding most deeper cortical surface placements toward GM/WM or GM/CSF boundaries, which directs a consistent reduction tendency of mean cortical thickness estimation; on the contrary, the lower resolution data will most probably provide a more coarse and rough evaluation in cortical surface reconstruction, resulting in a relatively thicker estimation. Although the differences of cortical thickness estimation at the diverse spatial resolution varied with one another, almost all led to roughly one-sixth to one-fifth significant reduction across the entire brain at the HR, independent to the pipelines we applied, which emphasizes on generally coherent improved accuracy in a data-independent manner and endeavors to cost-efficiency with quantitative opportunities.

Mitophagy protects against silver nanoparticle-induced hepatotoxicity by inhibiting mitochondrial ROS and the NLRP3 inflammasome.

Silver nanoparticles (AgNPs) have wide clinical applications because of their excellent antibacterial properties; however, they can cause liver inflammation in animals. Macrophages are among the main cells mediating inflammation and are also responsible for the phagocytosis of nanomaterials. The NLRP3 inflammasome is a major mechanism of inflammation, and its activation both induces cytokine release and triggers inflammatory cell death (i.e., pyroptosis). In previous studies, we demonstrated that mitophagy activation plays a protective role against AgNP-induced hepatotoxicity. However, the exact molecular mechanisms underlying these processes are not fully understood. In this study, we demonstrate that AgNP exposure induces NLRP3 inflammasome activation, mitochondrial damage and pyroptosis in vivo and in vitro. NLRP3 silencing or inhibiting mitochondrial reactive oxygen species (ROS) overproduction reduces PINK1-Parkin-mediated mitophagy. Meanwhile, the inhibition of mitophagy ROS production, mitochondrial, NLRP3-mediated inflammation, and pyroptosis in RAW264.7 cells were more pronounced than in the control group. These results suggest that PINK1-Parkin-mediated mitophagy plays a protective role by reducing AgNP-induced mitochondrial ROS and subsequent NLRP3 inflammasome activation.

Harnessing Oxylipins and Inflammation Modulation for Prevention and Treatment of Colorectal Cancer.

Colorectal cancer (CRC) is one of the most prevalent cancers worldwide, ranking as the third most malignant. The incidence of CRC has been increasing with time, and it is reported that Westernized diet and lifestyle play a significant role in its higher incidence and rapid progression. The intake of high amounts of omega-6 (n - 6) PUFAs and low levels of omega-3 (n - 3) PUFAs has an important role in chronic inflammation and cancer progression, which could be associated with the increase in CRC prevalence. Oxylipins generated from PUFAs are bioactive lipid mediators and have various functions, especially in inflammation and proliferation. Carcinogenesis is often a consequence of chronic inflammation, and evidence has shown the particular involvement of n - 6 PUFA arachidonic acid-derived oxylipins in CRC, which is further described in this review. A deeper understanding of the role and metabolism of PUFAs by their modifying enzymes, their pathways, and the corresponding oxylipins may allow us to identify new approaches to employ oxylipin-associated immunomodulation to enhance immunotherapy in cancer. This paper summarizes oxylipins identified in the context of the initiation, development, and metastasis of CRC. We further explore CRC chemo-prevention strategies that involve oxylipins as potential therapeutics.

Historical co-enrichment, source attribution, and risk assessment of critical nutrients and heavy metal/metalloids in lake sediments: insights from Chaohu Lake, China.

In Chinese freshwater lakes, eutrophication often coincides with heavy metal/metalloids (HM/Ms) pollution, yet the coevolution of critical nutrients (P, S, Se) and HM/Ms (Cd, Hg, etc.) remains understudied. To address this gap, we conducted a sedimentary chemistry analysis on a 30 cm-deep core, dating back approximately 200 years, retrieved from Chaohu Lake, China. The age-depth model revealed a gradual increase in deposition rates over time. Notably, the concentrations and enrichment factors (EFs) of most target elements surged in the uppermost ~ 15 cm layer, covering the period from 1953 to 2013, while both the concentrations and EFs in deeper layers remained relatively stable, except for Hg. This trend indicates a significant co-enrichment and near-synchronous increase in the levels and EFs of both nutrients and HM/Ms in the upper sediment layers since the mid-twentieth century. Anthropogenic factors were identified as the primary drivers of the enrichment of P, Se, Cd, Hg, Zn, and Te in the upper core, with their contributions also showing a coupled evolutionary trend over time. Conversely, geological activities governed the enrichment of elements in the lower half of the core. The gradual accumulation of anthropogenic Hg between the - 30 to - 15 cm layers might be attributed to global Hg deposition resulting from the industrial revolution. The ecological risk index (RI) associated with HM/Ms loading has escalated rapidly over the past 50 years, with Cd and Hg posing the greatest threats. Furthermore, the PMF model was applied to specifically quantify source contributions of these elements in the core, with anthropogenic and geogenic factors accounting for ~ 60 and ~ 40%, respectively. A good correlation (r2 = 0.87, p < 0.01) between the PMF and Ti-normalized method was observed, indicating their feasibility and cross-validation in source apportionment. Finally, we highlighted environment impact and health implications of the co-enrichment of nutrients and HM/Ms. This knowledge is crucial for developing strategies to protect freshwater ecosystems from the combined impacts of eutrophication and HM/Ms pollution, thereby promoting water environment and human health.

The profile of oral microbiome in Chinese elderly population associated with aging and systemic health status.

OBJECTIVE: The health of oral cavity is considered as an important indicator of aging. Oral microbiota is highly associated with the oral health, while the variation of oral microbiome in elderly population and characteristic microbes associated with aging remain unclear. SUBJECTS AND METHODS: In this study, 130 elderly subjects were recruited and divided into 3 groups according to their age: Stage I group (65 ≤ years < 70), Stage II group (70 ≤ years < 75), and Stage III group (75 ≤ years < 80). Their physiological indices were analyzed with using Illumina MiSeq platform and the oral microbiome was determined by high-throughput sequencing. RESULTS: Along with aging, the level of fasting blood glucose, systolic pressure and monocytes are significantly increased. No significant difference was detected on the whole structure of the oral microbiome among groups. While using Metastats and Spearman's correlation analysis, specific bacteria were identified as potential age- or health index-related bacterial genera including Fusobacterium, Parvimonas, Porphyromonas, Aminobacter, Collinsella, Clostridium and Acinetobacter. CONCLUSION: Our study revealed that the composition structure of salivary microbiota in elderly population was relatively stable while specific bacteria were correlated with age and health status, which is promising to be served as health indicators of the elderly after further exploration.

In Situ Coupling of Carbon Dots with Co-ZIF Nanoarrays Enabling Highly Efficient Oxygen Evolution Electrocatalysis.

Metal-organic frameworks (MOFs) are regarded as one promising class of precatalysts for electrocatalytic oxygen evolution reaction (OER), yet most of them suffer from poor conductivity and lack of coordinatively unsaturated metal sites, which hinders the fast electrochemical reconstruction and thus a poor OER activity. To address this issue, a unique heterocomposite has been constructed by in situ inserting carbon dots (CDs) into cobalt-based zeolitic imidazolate framework (Co-ZIF) nanosheet arrays (Co-ZIF/CDs/CC) in the presence of carbon cloth (CC) via one-pot coprecipitation for alkaline OER. Benefiting from the synergism between CDs and Co-ZIF subunits such as superior conductivity, strong charge interaction as well as abundant metal sites exposure, the Co-ZIF/CDs/CC exhibits an enhanced promotion effect for OER and contributes to the deep phase transformation from CDs-coupled Co-ZIF to CDs-coupled active CoOOH. As expected, the achieved Co-ZIF/CDs/CC only requires an overpotential of 226 mV to deliver 10 mA cm-2 in 1.0 M KOH, which is lower than that of Co-ZIF/CC and superior to most previously reported CC-supported MOF precatalysts. Moreover, it can also maintain a large current density of 100 mA cm-2 for 24 h with negligible activity decay.

Metabolic reprogramming and biosensor-assisted mutagenesis screening for high-level production of L-arginine in Escherichia coli.

L-arginine is a value-added amino acid with promising applications in the pharmaceutical and nutraceutical industries. Further unleashing the potential of microbial cell factories to make L-arginine production more competitive remains challenging due to the sophisticated intracellular interaction networks and the insufficient knowledge of global metabolic regulation. Here, we combined multilevel rational metabolic engineering with biosensor-assisted mutagenesis screening to exploit the L-arginine production potential of Escherichia coli. First, multiple metabolic pathways were systematically reprogrammed to redirect the metabolic flux into L-arginine synthesis, including the L-arginine biosynthesis, TCA cycle, and L-arginine export. Specifically, a toggle switch responding to special cellular physiological conditions was designed to dynamically control the expression of sucA and pull more carbon flux from the TCA cycle toward L-arginine biosynthesis. Subsequently, a biosensor-assisted high-throughput screening platform was designed and applied to further exploit the L-arginine production potential. The best-engineered ARG28 strain produced 132 g/L L-arginine in a 5-L bioreactor with a yield of 0.51 g/g glucose and productivity of 2.75 g/(L ⋅ h), which were the highest values reported so far. Through whole genome sequencing and reverse engineering, Frc frameshift mutant, PqiB A78P mutant, and RpoB P564T mutant were revealed for enhancing the L-arginine biosynthesis. Our study exhibited the power of coupling rational metabolic reprogramming and biosensor-assisted mutagenesis screening to unleash the cellular potential for value-added metabolite production.

Integration of metabolomics and transcriptomics analyses reveals sphingosine-1-phosphate-mediated S1PR2/PI3K/Akt pathway involved in Talaromyces marneffei infection of macrophages.

Talaromycosis is a fatal mycosis caused by the thermally dimorphic fungus Talaromyces marneffei (T. marneffei). The pathogenic mechanisms of talaromycosis are still poorly understood. This work combined metabolomics, transcriptomics, and verification experiments in vivo and in vitro to detect metabolic profiles and differentially expressed genes (DEGs) in T. marneffei infected and uninfected macrophages to explore possible pathogenesis and underlying mechanisms. A total of 256 differential metabolites (117 up-regulated and 148 down-regulated) and 1320 DEGs (1286 up-regulated and 34 down-regulated) were identified between the two groups. Integrative metabolomics and transcriptomics analysis showed sphingolipid signaling pathway is the most influential. Verification experiments showed that compared with the control group, the production of sphingosine-1-phosphate (S1P) and the expression of the S1PR1, S1PR2, phosphor-PI3K, and phosphor-Akt genes involved in the sphingolipid signaling pathway have significantly increased in the T. marneffei infection group (p < 0.05). T. marneffei activates the S1PR2/PI3K/Akt pathways in J774A.1 macrophage, regulation of the S1P singling might serve as a promising therapeutic strategy for talaromycosis.

Thalidomide promotes NLRP3/caspase-1-mediated pyroptosis of macrophages in Talaromyces marneffei infection.

Macrophage-derived inflammatory cytokines are critical for host defense against Talaromyces marneffei (T. marneffei) infection among HIV/AIDS patients, and excessive inflammatory cytokines are associated with poor outcomes of AIDS-associated talaromycosis. However, the underlying mechanisms of macrophage-caused pyroptosis and cytokine storm are poorly understood. Here, in the T. marneffei-infected mice and macrophages, we show that T. marneffei induced pyroptosis in macrophages through the NLRP3/caspase-1 pathway. The immunomodulatory drug thalidomide could promote the pyroptosis of macrophages infected T. marneffei. In T. marneffei-infected mice, the splenic macrophages underwent increasing pyroptosis as talaromycosis deteriorated. Thalidomide ameliorated inflammation of mice, while amphotericin B (AmB) in combination with thalidomide did not improve overall survival compared with AmB alone. Taken together, our findings suggest that thalidomide promotes NLRP3/caspase-1-mediated pyroptosis of macrophages in T. marneffei infection.

Enzyme hybrid nanoflowers and enzyme@metal-organic frameworks composites: fascinating hybrid nanobiocatalysts.

Hybrid nanomaterials have recently emerged as a new interface of nanobiocatalysis, serving as a host platform for enzyme immobilization. Enzyme immobilization in inorganic crystal nanoflowers and metal-organic frameworks (MOFs) has sparked the bulk of scientific interest due to their superior performances. Many breakthroughs have been achieved recently in the preparation of various types of enzyme@MOF and enzyme-hybrid nanoflower composites. However, it is unfortunate that there are few reviews in the literature related to enzyme@MOF and enzyme-hybrid nanoflower composites and their improved synthesis strategies and their applications in biotechnology. In this review, innovative synthetic strategies for enzyme@MOF composites and enzyme-hybrid nanoflower composites are discussed. Enzyme@MOF composites and enzyme-hybrid nanoflower composites are reviewed in terms of biotechnological applications and potential research directions. We are convinced that a fundamental study and application of enzyme@MOF composites and enzyme-hybrid nanoflower composites will be understood by the reader as a result of this work. The summary of different synthetic strategies for enzyme@MOF composites and enzyme-hybrid nanoflower composites and the improvement of their synthetic strategies will also benefit the readers and provide ideas and thoughts in the future research process.

Antifungal evaluation of quinoline-chalcone derivatives combined with FLC against drug-resistant Candida albicans.

With the widespread clinical use of FLC, the FLC-resistant C. albicans greatly increases the difficulty of treatment, and drug combination becomes an important method to treat C. albicans infection. In this work, we have prepared a series of quinoline-chalcone derivatives in good yields, and in vitro antifungal activity against C. albicans were evaluated. The results indicated that most title compounds combined with FLC showed good antifungal activity against drug-resistant C. albicans. Further mechanism researches demonstrated that 6a and 6c combined with FLC could significantly inhibited growth and biofilm formation of C. albicans, induce ROS accumulation, impair the mitochondrial membrane, and decrease intracellular ATP concentrations.

Unique genetic variants of lean nonalcoholic fatty liver disease: a retrospective cohort study.

We investigated the prevalence and clinical metabolic characteristics of lean nonalcoholic fatty liver disease (NAFLD) in an elderly Chinese population and assessed the relevance of lipid markers and genetic variation. All 5,338 community subjects underwent detailed clinical and laboratory examinations and were divided into three groups: lean (Body mass index (BMI) < 23 kg/m2, n = 2,012), overweight (BMI = 23-24.9 kg/m2, n = 1,354), and obese (BMI ≥ 25 kg/m2, n = 1,972). Single nucleotide polymorphisms were selected based on those reported in previous NAFLD or obesity genome-wide association studies. The frequencies of alleles and genotypes were calculated and statistically analyzed with Pearson's χ2 tests. One-way ANCOVA was used to test the association between positive SNPs and metabolic parameters in lean NAFLD individuals. Our results showed that the C allele frequency of rs2279026, the G allele of rs2279028, the C allele of rs780093, and the C allele frequency of rs1260326 were higher in obese NAFLD than in lean NAFLD (P < 0.05). In addition, we observed an association between the CC of rs1421085, TT of rs3751812, AA of rs8050136, and AA of rs9939609 genotypes in the FTO gene and low-density lipoprotein levels (P < 0.05). In conclusion, our findings provide a unique perspective on the prevalence, genetic characteristics, and metabolic profile of NAFLD in older lean individuals in China. This is the first study to examine the association between genetic variants in the FTO, TFAP2B and GCKR genes and NAFLD in a cohort of lean individuals.

Association between myeloperoxidase and the risks of ischemic stroke, heart failure, and atrial fibrillation: A Mendelian randomization study.

BACKGROUND AND AIMS: The causality between myeloperoxidase (MPO) and cardiovascular disease still remains unclear. We performed a two-sample Mendelian randomization (MR) study to estimate the potential causal effect of MPO on the risks of ischemic stroke, ischemic stroke subtypes, heart failure (HF), and atrial fibrillation (AF). METHODS AND RESULTS: Seventeen independent single-nucleotide polymorphisms associated with MPO levels were identified as instrumental variables from a European-descent genome-wide association study. Summary-level data on ischemic stroke originated from the Multiancestry Genome-wide Association Study of Stroke Consortium with 440 328 European individuals. We used the inverse-variance weighted method to assess the potential causality of plasma MPO with ischemic stroke and its subtypes in the main analysis. Genetically determined higher plasma MPO concentration was significantly associated with increased risks of ischemic stroke (odds ratio [OR] per standard deviation [SD] increase, 1.05; 95% confidence interval [CI], 1.02-1.09; P = 0.002) and cardioembolic stroke (CES) (OR per SD increase, 1.10; 95% CI, 1.03-1.18; P = 0.005), but was not associated with risks of large artery stroke or small vessel stroke. In the secondary analysis, MPO was associated with a high risk of HF (OR per SD increase, 1.05; 95% CI, 1.02-1.07; P = 0.001) and AF (OR per SD increase, 1.04; 95% CI, 1.01-1.07; P = 0.004). MR-Egger regression showed no directional pleiotropy for all associations, and the sensitivity analyses further confirmed these findings. CONCLUSION: High plasma MPO levels were potentially associated with increased risks of ischemic stroke, CES, HF, and AF, suggesting that MPO plays an important role in the development of cardiovascular disease.