Differential expression profiles and bioinformatics analysis of tRNA-derived small RNAs in epicardial fat of patients with atrial fibrillation.

The exact processes underlying atrial fibrillation (AF) are still unclear. It has been suggested that epicardial adipose tissue (EAT) may contribute to arrhythmias and can release various bioactive molecules, including exosomes containing tRNA-derived small RNAs (tsRNAs). Numerous studies have indicated that these tsRNAs can significantly affect key cellular functions. However, there is currently no research investigating the relationship between tsRNAs from EAT and AF. In order to explore the regulatory mechanisms of tsRNAs from EAT associated with AF, we conducted RNA-sequencing analysis on EAT samples collected from 6 AF patients and 6 control subjects with sinus rhythm. Our analysis revealed an upregulation of 146 tsRNAs and a downregulation of 126 tsRNAs in AF. Furthermore, we randomly selected four tsRNAs (tRF-SeC-TCA-001, tiRNA-Gly-CCC-003, tRF-Gly-GCC-002, and tRF-Tyr-GTA-007) for validation using quantitative reverse transcription-polymerase chain reaction. Following this, bioinformatic analyses revealed that the target genes of these tsRNAs were prominently involved in the regulation of cell adhesion and various cellular processes mediated by plasma membrane adhesion molecules. Additionally, based on KEGG analysis, it was suggested that the majority of these target genes might contribute to the pathogenesis of AF through processes such as glycosaminoglycan biosynthesis, AMP-activated protein kinase activity, and the insulin signaling pathway. Our results elucidate changes in the expression profiles of tsRNAs within EAT samples obtained from AF patients, and they forecast potential target genes and interactions between tsRNAs and mRNA within EAT that could contribute to the pathogenesis of AF.

Transcriptionally Active Human Papillomavirus Infection in a Minority of Esophageal Squamous Cell Carcinomas in North America.

The role of Human papillomavirus (HPV) infection in esophageal squamous cell carcinoma (ESCC) is a topic of ongoing debate. This study used two screening approaches to look for evidence of HPV infection in esophageal squamous cell carcinoma. We initially checked for HPV infection in a randomly selected group of 53 ESCC cases. We did not detect any tumors positive for high-risk HPV. However, during clinical practice, we identified an HPV-positive ESCC in the distal esophagus, which tested positive for HPV16. This index case was TP53 wild-type, as determined by next-generation DNA sequencing (NGS). Since TP53 mutations are rare in other HPV-driven cancers, we improved our screening method by limiting our screen to a subset of ESCC cases without TP53 mutations. A second screen of 95 ESCCs (from 93 patients) sequenced by NGS revealed an additional 7 ESCCs with TP53 wild-type status (7.3% of the total). Of the 7 cases, 2 cases were found to be high-risk HPV positive. Both patients also tested positive for circulating cell-free HPV DNA and had a complete response to neoadjuvant chemoradiation. The index patient had microscopic residual tumor following neoadjuvant therapy. The patient underwent adjuvant immunotherapy and remained disease free after 22 months of surveillance. This study affirms the transcriptionally active status of high-risk HPV in a minority of ESCC patients in North America.

Corilagin alleviates atherosclerosis by inhibiting NLRP3 inflammasome activation via the Olfr2 signaling pathway in vitro and in vivo.

Introduction: Atherosclerosis, a leading cause of global cardiovascular mortality, is characterized by chronic inflammation. Central to this process is the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, which significantly influences atherosclerotic progression. Recent research has identified that the olfactory receptor 2 (Olfr2) in vascular macrophages is instrumental in driving atherosclerosis through NLRP3- dependent IL-1 production. Methods: To investigate the effects of Corilagin, noted for its anti-inflammatory attributes, on atherosclerotic development and the Olfr2 signaling pathway, our study employed an atherosclerosis model in ApoE-/- mice, fed a high-fat, high-cholesterol diet, alongside cellular models in Ana-1 cells and mouse bone marrow-derived macrophages, stimulated with lipopolysaccharides and oxidized low-density lipoprotein. Results: The vivo and vitro experiments indicated that Corilagin could effectively reduce serum lipid levels, alleviate aortic pathological changes, and decrease intimal lipid deposition. Additionally, as results showed, Corilagin was able to cut down expressions of molecules associated with the Olfr2 signaling pathway. Discussion: Our findings indicated that Corilagin effectively inhibited NLRP3 inflammasome activation, consequently diminishing inflammation, macrophage polarization, and pyroptosis in the mouse aorta and cellular models via the Olfr2 pathway. This suggests a novel therapeutic mechanism of Corilagin in the treatment of atherosclerosis.

Clinical Value of the Quantitative Flow Ratio to Predict Long-term Target Vessel Failure in Patients with In-stent Restenosis after Drug-coated Balloon Angioplasty.

OBJECTIVE: The study sought to investigate the clinical predictive value of quantitative flow ratio (QFR) for the long-term target vessel failure (TVF) outcome in patients with in-stent restenosis (ISR) by using drug-coated balloon (DCB) treatment after a long-term follow-up. METHODS: This was a retrospective study. A total of 186 patients who underwent DCB angioplasty for ISR in two hospitals from March 2014 to September 2019 were enrolled. The QFR of the entire target vessel was measured offline. The primary endpoint was TVF, including target vessel-cardiac death (TV-CD), target vessel-myocardial infarction (TV-MI), and clinically driven-target vessel revascularization (CD-TVR). RESULTS: The follow-up time was 3.09±1.53 years, and 50 patients had TVF. The QFR immediately after percutaneous coronary intervention (PCI) was significantly lower in the TVF group than in the no-TVF group. Multivariable Cox regression analysis indicated that the QFR immediately after PCI was an excellent predictor for TVF after the long-term follow-up [hazard ratio (HR): 5.15×10-5 (6.13×10-8-0.043); P<0.01]. Receiver-operating characteristic (ROC) curve analysis demonstrated that the optimal cut-off value of the QFR immediately after PCI for predicting the long-term TVF was 0.925 (area under the curve: 0.886, 95% confidence interval: 0.834-0.938; sensitivity: 83.40%, specificity: 88.00; P<0.01). In addition, QFR≤0.925 post-PCI was strongly correlated with the TVF, including TV-MI and CD-TVR (P<0.01). CONCLUSION: The QFR immediately after PCI showed a high predictive value of TVF after a long-term follow-up in ISR patients who underwent DCB angioplasty. A lower QFR immediately after PCI was associated with a worse TVF outcome.

Characterization of the aroma-active compounds in Xiaokeng green tea by three pretreatment methods combined with gas chromatography-olfactometry (GC-O).

Chinese Xiaokeng green tea (XKGT) possesses elegant and fascinating aroma characteristics, but its key odorants are still unknown. In this study, 124 volatile compounds in the XKGT infusion were identified by headspace-solid phase microextraction (HS-SPME), stir bar sorptive extraction (SBSE), and solvent extraction-solid phase extraction (SE-SPE) combined with gas chromatography-mass spectrometry (GC-MS). Comparing these three pretreatments, we found HS-SPME was more efficient for headspace compounds while SE-SPE was more efficient for volatiles with higher boiling points. Furthermore, SBSE showed more sensitive to capture ketones then was effective to the application of pretreatment of aroma analysis in green tea. The aroma intensities (AIs) were further identified by gas chromatography-olfactometry (GC-O). According to the AI and relative odor activity value (rOAV), 27 compounds were identified as aroma-active compounds. Quantitative descriptive analysis (QDA) showed that the characteristic aroma attributes of XKGT were chestnut-like, corn-like, fresh, and so on. The results of network analysis showed that (E, Z)-2,6-nonadienal, nonanal, octanal and nerolidol were responsible for the fresh aroma. Similarly, dimethyl sulfide, (E, E)-2,4-heptadienal, (E)-2-octenal and ß-cyclocitral contributed to the corn-like aroma. Furthermore, indole was responsible for the chestnut-like and soybean-like aroma. This study contributes to a better understanding of the molecular mechanism of the aroma characteristics of XKGT.

Screening and diagnosis of cardiovascular disease using artificial intelligence-enabled cardiac magnetic resonance imaging.

Cardiac magnetic resonance imaging (CMR) is the gold standard for cardiac function assessment and plays a crucial role in diagnosing cardiovascular disease (CVD). However, its widespread application has been limited by the heavy resource burden of CMR interpretation. Here, to address this challenge, we developed and validated computerized CMR interpretation for screening and diagnosis of 11 types of CVD in 9,719 patients. We propose a two-stage paradigm consisting of noninvasive cine-based CVD screening followed by cine and late gadolinium enhancement-based diagnosis. The screening and diagnostic models achieved high performance (area under the curve of 0.988 ± 0.3% and 0.991 ± 0.0%, respectively) in both internal and external datasets. Furthermore, the diagnostic model outperformed cardiologists in diagnosing pulmonary arterial hypertension, demonstrating the ability of artificial intelligence-enabled CMR to detect previously unidentified CMR features. This proof-of-concept study holds the potential to substantially advance the efficiency and scalability of CMR interpretation, thereby improving CVD screening and diagnosis.

Design, synthesis and bioactivity evaluation of novel monomethyl auristatin F analogues.

Monomethyl auristatin F (MMAF), a synthetic analogue of the natural compound dolastatin 10, has garnered significant attention in cancer research due to its high potency in vitro. While previous studies have focused on modifying the N-terminal extension of the amino group and the C-terminal modification of the carboxyl group, there has been limited exploration into modifying the P1 and P5 side chains. In this study, we substituted the valine residue at the P1 position with various natural or unnatural amino acids and introduced triazole functional groups at the P5 side chain. Compounds 11k and 18d exhibited excellent inhibition on tubulin. Additionally, compound 18d demonstrated enhanced cytotoxicity against HCT116 cells compared to the parent compound MMAF, suggesting its potential as a cytotoxic payload for further antibody-drug conjugates (ADCs) development.

Facile Semiconductor p-n Homojunction Nanowires with Strategic p-Type Doping Engineering Combined with Surface Reconstruction for Biosensing Applications.

Photosensors with versatile functionalities have emerged as a cornerstone for breakthroughs in the future optoelectronic systems across a wide range of applications. In particular, emerging photoelectrochemical (PEC)-type devices have recently attracted extensive interest in liquid-based biosensing applications due to their natural electrolyte-assisted operating characteristics. Herein, a PEC-type photosensor was carefully designed and constructed by employing gallium nitride (GaN) p-n homojunction semiconductor nanowires on silicon, with the p-GaN segment strategically doped and then decorated with cobalt-nickel oxide (CoNiOx). Essentially, the p-n homojunction configuration with facile p-doping engineering improves carrier separation efficiency and facilitates carrier transfer to the nanowire surface, while CoNiOx decoration further boosts PEC reaction activity and carrier dynamics at the nanowire/electrolyte interface. Consequently, the constructed photosensor achieves a high responsivity of 247.8 mA W-1 while simultaneously exhibiting excellent operating stability. Strikingly, based on the remarkable stability and high responsivity of the device, a glucose sensing system was established with a demonstration of glucose level determination in real human serum. This work offers a feasible and universal approach in the pursuit of high-performance bio-related sensing applications via a rational design of PEC devices in the form of nanostructured architecture with strategic doping engineering.

Analysis of sinusoidal post-buckling deformation of horizontal coiled tubing with initial residual bending.

In the process of horizontal well construction, the working environment in the well is very complicated. It is difficult to determine the actual deformation and force of the coiled tubing in the wellbore from the load change at the wellhead along. In addition, the coiled tubing wrapped around the reel and entering the wellbore through the injection head may cause an initial residual bending. In this paper, the mathematical model of the coiled tubing under axial load during buckling deformation is established, and the analytical solution with the time term is derived by reasonable simplification of the model. The effect of residual bending on the post-sinusoidal buckling of the coiled tubing in the horizontal well was investigated using the separation variable method. The effect of residual bending variations on the well wall contact forces is analyzed. The research shows that the initial parameter Г is the main factor influencing the post-sinusoidal buckling of the coiled tubing with residual bending. The larger the parameter value Г, the greater the effect of the residual bending on the post-sinusoidal buckling deformation of the coiled tubing, and the earlier the critical point of the mixed sinusoidal-helical buckling of the coiled tubing appears. The compression velocity of the coiled tubing has a significant effect on the well wall contact force. The faster the compression, the greater the contact force. By introducing the time term and the separation variable, this paper provides a new method and theoretical basis for further study of the process of entering sinusoidal-helical buckling of the coiled tubing with initial residual bending.

Polycyclic aromatic hydrocarbons exposure and arterial stiffness-related plasma miRNAs: A panel study.

The underlying mechanisms between polycyclic aromatic hydrocarbons (PAHs) exposure and arterial stiffness are poorly understood. We carried out a panel study involving three repeated surveys to examine the associations of individual and mixture of PAHs exposure with arterial stiffness-related miRNAs among 123 community adults. In linear mixed-effect (LME) models, we found that urinary 9-hydroxyfluorene (9-OHFlu), 2-hydroxyphenanthrene (2-OHPh), 9-hydroxyphenanthrene (9-OHPh) at lag 0 day were positively linked to miR-146a and/or miR-222. The Bayesian kernel machine regression (BKMR) analyses revealed positive overall associations of PAHs mixture at lag 0 day with miR-146a and miR-222, and urinary 9-OHFlu contributed the most. In addition, an inter-quartile range (IQR) increase in urinary 9-OHFlu at lag 0 day was associated with elevated miR-146a and miR-222 by 0.16 (95% CI: 0.02, 0.30) to 0.34 (95% CI: 0.13, 0.54). Accordingly, exposure to PAHs, especially 9-OHFlu at lag 0 day, was related to elevated arterial stiffness-related plasma miRNAs.

High risk features in colorectal adenomatous polyps: A multi-institutional study.

High risk features in colorectal adenomatous polyps include size >1 cm and advanced histology: high-grade dysplasia and villous architecture. We investigated whether the diagnostic rates of advanced histology in colorectal adenomatous polyps were similar among institutions across the United States, and if not, could differences be explained by patient age, polyp size, and/or CRC rate. Nine academic institutions contributed data from three pathologists who had signed out at least 100 colorectal adenomatous polyps each from 2018 to 2019 taken from patients undergoing screening colonoscopy. For each case, we recorded patient age and sex, polyp size and location, concurrent CRC, and presence or absence of HGD and villous features. A total of 2700 polyps from 1886 patients (mean age: 61 years) were collected. One hundred twenty-four (5 %) of the 2700 polyps had advanced histology, including 35 (1 %) with HGD and 101 (4 %) with villous features. The diagnostic rate of advanced histology varied by institution from 1.7 % to 9.3 % (median: 4.3 %, standard deviation [SD]: 2.5 %). The rate of HGD ranged from 0 % to 3.3 % (median: 1 %, SD: 1.2 %), while the rate of villous architecture varied from 1 % to 8 % (median: 3.7 %, SD: 2.5 %). In a multivariate analysis, the factor most strongly associated with advanced histology was polyp size >1 cm with an odds ratio (OR) of 31.82 (95 % confidence interval [CI]: 20.52-50.25, p < 0.05). Inter-institutional differences in the rate of polyps >1 cm likely explain some of the diagnostic variance, but pathologic subjectivity may be another contributing factor.

Identification of Novel Peptides in Distillers' Grains as Antioxidants, α-Glucosidase Inhibitors, and Insulin Sensitizers: In Silico and In Vitro Evaluation.

Distillers' grains are rich in protein and constitute a high-quality source of various bioactive peptides. The purpose of this study is to identify novel bioactive peptides with α-glucosidase inhibitory, antioxidant, and insulin resistance-ameliorating effects from distiller's grains protein hydrolysate. Three novel peptides (YPLPR, AFEPLR, and NDPF) showed good potential bioactivities, and the YPLPR peptide had the strongest bioactivities, whose IC50 values towards α-glucosidase inhibition, radical scavenging rates of 2,2'-azino-bis (3-ethylbenzothiazoline-6- sulfonic acid) (ABTS) and 2,2-diphenyl-1-picrylhydrazyl (DPPH) were about 5.31 mmol/L, 6.05 mmol/L, and 7.94 mmol/L, respectively. The glucose consumption of HepG2 cells treated with YPLPR increased significantly under insulin resistance condition. Moreover, the YPLPR peptide also had a good scavenging effect on intracellular reactive oxygen species (ROS) induced by H2O2 (the relative contents: 102.35% vs. 100%). Molecular docking results showed that these peptides could stably combine with α-glucosidase, ABTS, and DPPH free radicals, as well as related targets of the insulin signaling pathway through hydrogen bonding and van der Waals forces. This research presents a potentially valuable natural resource for reducing oxidative stress damage and regulating blood glucose in diabetes, thereby increasing the usage of distillers' grains peptides and boosting their economic worth.

Microbial interactions facilitating efficient methane driven denitrification via in-situ utilization of short chain fatty acids.

High nitrate pollution in agriculture and industry poses a challenge to emerging methane oxidation coupled denitrification. In this study, an efficient nitrate removal efficiency of 100 % was achieved at an influent loading rate of 400 mg-N/L·d, accompanied by the production of short chain fatty acids (SCFAs) with a maximum value of 80.9 mg/L. Batch tests confirmed that methane was initially converted to acetate, which then served as a carbon source for denitrification. Microbial community characterization revealed the dominance of heterotrophic denitrifiers, including Simplicispira (22.8 %), Stappia (4.9 %), and the high­nitrogen-tolerant heterotrophic denitrifier Diaphorobacter (19.0 %), at the nitrate removal rate of 400 mg-N/L·d. Notably, the low abundance of methanotrophs ranging from 0.24 % to 3.75 % across all operational stages does not fully align with the abundance of pmoA genes, suggesting the presence of other functional microorganisms capable of methane oxidation and SCFAs production. These findings could facilitate highly efficient denitrification driven by methane and contributed to the development of denitrification using methane as an electron donor.

Prediction method for the tension force of support ropes in flexible rockfall barriers based on full-scale experiments and numerical analysis.

This paper proposes a prediction method for the tension force of support ropes in flexible rockfall barriers. The method is based on two full-scale model tests with an impact energy of 3000 kJ, as well as 36 set numerical models featuring varying lengths and impact energies. From the results of full scale tests and numerical models, it is inferred that the tension force at the end of the support rope is significantly less than that at the point of impact, exhibiting an approximate Gaussian attenuation distribution with propagation distance. To account for the attenuation of tensile forces in support ropes, a tensile attenuation coefficient is defined. Through comparative analysis of data obtained from 36 models with varying impact energies and propagation distances, the average attenuation coefficient for the upper support rope is determined to be approximately 0.7, while the average coefficient for the lower support rope is around 0.8. Utilizing the least squares method, a prediction method for the tension force of support ropes in flexible rockfall barriers is established. This method takes into account both the propagation distance and impact energy, enabling accurate predictions of the tensile behavior of the ropes under different conditions. This prediction model provides valuable insights for engineers in the design and optimization of these flexible barriers for rockfall mitigation.

Turning Ultra-Low Coercivity and Ultra-High Temperature Stability Within 897 K via Continuous Crystal Ordering Fluctuations.

High-performance soft magnetic materials are important for energy conservation and emission reduction. One challenge is achieving a combination of reliable temperature stability, high resistivity, high Curie temperature, and high saturation magnetization in a single material, which often comes at the expense of intrinsic coercivity-a typical trade-off in the family of soft magnetic materials with homogeneous microstructures. Herein, a nanostructured FeCoNiSiAl complex concentrated alloy is developed through a hierarchical structure strategy. This alloy exhibits superior soft magnetic properties up to 897 K, maintaining an ultra-low intrinsic coercivity (13.6 A m-1 at 297 K) over a wide temperature range, a high resistivity (138.08 µΩ cm-1 at 297 K) and the saturation magnetization with only a 16.7% attenuation at 897 K. These unusual property combinations are attributed to the dual-magnetic-state nature with exchange softening due to continuous crystal ordering fluctuations at the atomic scale. By deliberately controlling the microstructure, the comprehensive performance of the alloy can be tuned and controlled. The research provides valuable guidance for the development of soft magnetic materials for high-temperature applications and expands the potential applications of related functional materials in the field of sustainable energy.

Interruption after Short-Term Nitrogen Additions Improves Ecological Stability of Larix olgensis Forest Soil by Affecting Bacterial Communities.

Atmospheric nitrogen deposition can alter soil microbial communities and further impact the structure and function of forest ecosystems. However, most studies are focused on positive or negative effects after nitrogen addition, and few studies pay attention to its interruption. In order to investigate whether interruption after different levels of short-term N additions still benefit soil health, we conducted a 2-year interruption after a 4-year short-term nitrogen addition (10 and 20 kg N·hm-2·yr-1) experiment; then, we compared soil microbial diversity and structure and analyzed soil physicochemical properties and their correlations before and after the interruption in Larix olgensis forest soil in northeast China. The results showed that soil ecological stabilization of Larix olgensis forest further improved after the interruption compared to pre-interruption. The TN, C:P, N:P, and C:N:P ratios increased significantly regardless of the previous nitrogen addition concentration, and soil nutrient cycling was further promoted. The relative abundance of the original beneficial microbial taxa Gemmatimonas, Sphingomonas, and Pseudolabrys increased; new beneficial bacteria Ellin6067, Massilia, Solirubrobacter, and Bradyrhizobium appeared, and the species of beneficial soil microorganisms were further improved. The results of this study elucidated the dynamics of the bacterial community before and after the interruption of short-term nitrogen addition and could provide data support and a reference basis for forest ecosystem restoration strategies and management under the background of global nitrogen deposition.

Direct Selective Epitaxy of 2D Sb2Te3 onto Monolayer WS2 for Vertical p-n Heterojunction Photodetectors.

Two-dimensional transition metal dichalcogenides (2D-TMDs) possess appropriate bandgaps and interact via van der Waals (vdW) forces between layers, effectively overcoming lattice compatibility challenges inherent in traditional heterojunctions. This property facilitates the creation of heterojunctions with customizable bandgap alignments. However, the prevailing method for creating heterojunctions with 2D-TMDs relies on the low-efficiency technique of mechanical exfoliation. Sb2Te3, recognized as a notable p-type semiconductor, emerges as a versatile component for constructing diverse vertical p-n heterostructures with 2D-TMDs. This study presents the successful large-scale deposition of 2D Sb2Te3 onto inert mica substrates, providing valuable insights into the integration of Sb2Te3 with 2D-TMDs to form heterostructures. Building upon this initial advancement, a precise epitaxial growth method for Sb2Te3 on pre-existing WS2 surfaces on SiO2/Si substrates is achieved through a two-step chemical vapor deposition process, resulting in the formation of Sb2Te3/WS2 heterojunctions. Finally, the development of 2D Sb2Te3/WS2 optoelectronic devices is accomplished, showing rapid response times, with a rise/decay time of 305 µs/503 µs, respectively.

Periodontal pathogen Fusobacterium nucleatum infection accelerates hepatic steatosis in high-fat diet-fed ApoE knockout mice by inhibiting Nrf2/Keap1 signaling.

AIMS: This study sought to explore the impact of Fusobacterium nucleatum on hepatic steatosis in apolipoprotein E (ApoE) knockout (KO) mice induced by a high-fat diet (HFD) and elucidate the underlying mechanism. METHODS: ApoE KO mice, on a HFD, received F. nucleatum oral inoculation every other day. After 24 weeks, body weight, liver weight, and liver index were assessed. Serum biochemistry and pro-inflammatory factors in serum and liver were analyzed. The histopathology of right maxilla and live were performed. Oil red O, immunohistochemistry, and immunofluorescence staining for the liver were conducted. Myeloperoxidase (MPO) activity, apoptosis, lipid reactive oxygen species (ROS), ROS, lipid peroxides, and hepatic lipids were also evaluated. Liver inflammation, fibrosis, de novo lipogenesis (DNL)-related molecule, and Nrf2/Keap1-related signaling molecule gene/protein expression were determined by real-time PCR (RT-PCR) and/or Western blot (WB) analysis. RESULTS: HFD-fed ApoE KO mice infected by F. nucleatum demonstrated significant changes, including increased body and liver weight, elevated proinflammatory factors and lipids in serum and liver, as well as neutrophil infiltration, fibrosis, apoptosis, oxidative stress, and lipid peroxidation in the liver. Additionally, F. nucleatum stimulates hepatic lipid accumulation and activates de novo lipogenesis (DNL), while simultaneously suppressing the Nrf2/Keap1 antioxidant pathway. CONCLUSION: In conclusion, our study reveals that oral inoculation of F. nucleatum might promote hepatic steatosis by inhibiting Nrf2/Keap1 pathway.

Chemerin Levels in Individuals with Type 2 Diabetes and a Normal Weight versus Individuals with Type 2 Diabetes and Obesity: An Observational, Cross-Sectional Study.

Chemerin acts as both a chemotactic agent and an adipokine that undergoes proteolytic cleavage, converting inactive precursors into their active forms before being subsequently inactivated. Elevated chemerin levels are linked to obesity and type 2 diabetes mellitus (T2D). This study aimed to elucidate the effects of T2D and obesity on chemerin levels by comparing plasma samples from individuals with a normal weight and T2D (BMI < 25; NWD group n = 22) with those from individuals who are overweight or obese and have T2D (BMI ≥ 25; OWD group n = 39). The total chemerin levels were similar in the NWD and OWD groups, suggesting that T2D may equalize the chemerin levels irrespective of obesity status. The cleavage of chemerin has been previously linked to myocardial infarction and stroke in NWD, with potential implications for inflammation and mortality. OWD plasma exhibited lower levels of cleaved chemerin than the NWD group, suggesting less inflammation in the OWD group. Here, we showed that the interaction between obesity and T2D leads to an equalization in the total chemerin levels. The cleaved chemerin levels and the associated inflammatory state, however, differ significantly, underscoring the complex relationship between chemerin, T2D, and obesity.

Concomitant NAFLD Facilitates Liver Metastases and PD-1-Refractory by Recruiting MDSCs via CXCL5/CXCR2 in Colorectal Cancer.

BACKGROUND & AIMS: Both nonalcoholic fatty liver disease (NAFLD) and colorectal cancer (CRC) are prevalent worldwide. The effects of concomitant NAFLD on the risk of colorectal liver metastasis (CRLM) and its mechanisms have not been definitively elucidated. METHODS: We observed the effect of concomitant NAFLD on CRLM in the mouse model and explored the underlying mechanisms of specific myeloid-derived suppressor cells (MDSCs) recruitment and then tested the therapeutic application based on the mechanisms. Finally we validated our findings in the clinical samples. RESULTS: Here we prove that in different mouse models, NAFLD induces F4/80+ Kupffer cells to secret chemokine CXCL5 and then recruits CXCR2+ MDSCs to promote the growth of CRLM. CRLM with NAFLD background is refractory to the anti-PD-1 monoclonal antibody treatment, but when combined with Reparixin, an inhibitor of CXCR1/2, dual therapy cures the established CRLM in mice with NAFLD. Our clinical studies also indicate that fatty liver diseases increase the infiltration of CXCR2+ MDSCs, as well as the hazard of liver metastases in CRC patients. CONCLUSIONS: Collectively, our findings highlight the significance of selective CXCR2+/CD11b+/Gr-1+ subset myeloid cells in favoring the development of CRLM with NAFLD background and identify a pharmaceutical medicine that is already available for the clinical trials and potential treatment.