Negative regulation of AMPK signaling by high glucose via E3 ubiquitin ligase MG53.

As a master regulator of metabolism, AMP-activated protein kinase (AMPK) is activated upon energy and glucose shortage but suppressed upon overnutrition. Exaggerated negative regulation of AMPK signaling by nutrient overload plays a crucial role in metabolic diseases. However, the mechanism underlying the negative regulation is poorly understood. Here, we demonstrate that high glucose represses AMPK signaling via MG53 (also called TRIM72) E3-ubiquitin-ligase-mediated AMPKα degradation and deactivation. Specifically, high-glucose-stimulated reactive oxygen species (ROS) signals AKT to phosphorylate AMPKα at S485/491, which facilitates the recruitment of MG53 and the subsequent ubiquitination and degradation of AMPKα. In addition, high glucose deactivates AMPK by ROS-dependent suppression of phosphorylation of AMPKα at T172. These findings not only delineate the mechanism underlying the impairment of AMPK signaling in overnutrition-related diseases but also highlight the significance of keeping the yin-yang balance of AMPK signaling in the maintenance of metabolic homeostasis.

Bifunctional Electrocatalysts for Overall and Hybrid Water Splitting.

Electrocatalytic water splitting driven by renewable electricity has been recognized as a promising approach for green hydrogen production. Different from conventional strategies in developing electrocatalysts for the two half-reactions of water splitting (e.g., the hydrogen and oxygen evolution reactions, HER and OER) separately, there has been a growing interest in designing and developing bifunctional electrocatalysts, which are able to catalyze both the HER and OER. In addition, considering the high overpotentials required for OER while limited value of the produced oxygen, there is another rapidly growing interest in exploring alternative oxidation reactions to replace OER for hybrid water splitting toward energy-efficient hydrogen generation. This Review begins with an introduction on the fundamental aspects of water splitting, followed by a thorough discussion on various physicochemical characterization techniques that are frequently employed in probing the active sites, with an emphasis on the reconstruction of bifunctional electrocatalysts during redox electrolysis. The design, synthesis, and performance of diverse bifunctional electrocatalysts based on noble metals, nonprecious metals, and metal-free nanocarbons, for overall water splitting in acidic and alkaline electrolytes, are thoroughly summarized and compared. Next, their application toward hybrid water splitting is also presented, wherein the alternative anodic reactions include sacrificing agents oxidation, pollutants oxidative degradation, and organics oxidative upgrading. Finally, a concise statement on the current challenges and future opportunities of bifunctional electrocatalysts for both overall and hybrid water splitting is presented in the hope of guiding future endeavors in the quest for energy-efficient and sustainable green hydrogen production.

Distribution of Antibiotic-Resistant Genes in Intestines of Infants and Influencing Factors.

The objective of this study is to assess the prevalence of antibiotic-resistant genes (ARGs) in the intestines of infants and the factors affecting their distribution. Breast milk and infant stool samples were collected from nine full-term, healthy mother-infant pairs. The bacterial distribution and various types of ARGs present in the samples were analyzed using metagenomic next-generation sequencing. Over a period spanning from 2 to 240 d after birth, a total of 273 types of ARGs were identified in both infant feces and breast milk, exhibiting a trend of increasing prevalence over time. High concentrations of representative ARG populations were identified in the intestines of infants, especially at 12-15 d after birth. These populations included APH3-Ib, tetW/N/W, mphA, and Haemophilus influenzae PBP3, and multiple ARG Escherichia coli soxS that were resistant to common clinically used aminoglycoside, tetracycline, macrolide, and beta-lactam antibiotics. Gammaproteobacteria and Bacilli, especially Enterococcus, Staphylococcus, Acinetobacter, Streptococcus, and Escherichia were among the identified ARG carriers. Maternal age and body mass index (present and before pregnancy), infant sex, maternal consumption of probiotic yogurt during pregnancy, and lactation might be substantial factors influencing the occurrence of ARG-carrying bacteria and ARG distribution in the infant feces. These results indicate that environmental factors may influence the distribution of ARG-carrying bacteria and ARGs themselves in infants during early life. Providing appropriate recommendations regarding maternal age, body mass index during pregnancy, and use of probiotic products could potentially mitigate the transmission of antibiotic-resistant microbiota and ARGs, thereby diminishing the risk of antibiotic-resistant infections and safeguarding children's health.

Perovskite light-emitting diodes with external quantum efficiency exceeding 20 per cent.

Metal halide perovskite materials are an emerging class of solution-processable semiconductors with considerable potential for use in optoelectronic devices1-3. For example, light-emitting diodes (LEDs) based on these materials could see application in flat-panel displays and solid-state lighting, owing to their potential to be made at low cost via facile solution processing, and could provide tunable colours and narrow emission line widths at high photoluminescence quantum yields4-8. However, the highest reported external quantum efficiencies of green- and red-light-emitting perovskite LEDs are around 14 per cent7,9 and 12 per cent8, respectively-still well behind the performance of organic LEDs10-12 and inorganic quantum dot LEDs13. Here we describe visible-light-emitting perovskite LEDs that surpass the quantum efficiency milestone of 20 per cent. This achievement stems from a new strategy for managing the compositional distribution in the device-an approach that simultaneously provides high luminescence and balanced charge injection. Specifically, we mixed a presynthesized CsPbBr3 perovskite with a MABr additive (where MA is CH3NH3), the differing solubilities of which yield sequential crystallization into a CsPbBr3/MABr quasi-core/shell structure. The MABr shell passivates the nonradiative defects that would otherwise be present in CsPbBr3 crystals, boosting the photoluminescence quantum efficiency, while the MABr capping layer enables balanced charge injection. The resulting 20.3 per cent external quantum efficiency represents a substantial step towards the practical application of perovskite LEDs in lighting and display.

Measurements of the gravitational constant using two independent methods.

The Newtonian gravitational constant, G, is one of the most fundamental constants of nature, but we still do not have an accurate value for it. Despite two centuries of experimental effort, the value of G remains the least precisely known of the fundamental constants. A discrepancy of up to 0.05 per cent in recent determinations of G suggests that there may be undiscovered systematic errors in the various existing methods. One way to resolve this issue is to measure G using a number of methods that are unlikely to involve the same systematic effects. Here we report two independent determinations of G using torsion pendulum experiments with the time-of-swing method and the angular-acceleration-feedback method. We obtain G values of 6.674184 × 10-11 and 6.674484 × 10-11 cubic metres per kilogram per second squared, with relative standard uncertainties of 11.64 and 11.61 parts per million, respectively. These values have the smallest uncertainties reported until now, and both agree with the latest recommended value within two standard deviations.

Vibrational relaxation dynamics in layered perovskite quantum wells.

Organic-inorganic layered perovskites, or Ruddlesden-Popper perovskites, are two-dimensional quantum wells with layers of lead-halide octahedra stacked between organic ligand barriers. The combination of their dielectric confinement and ionic sublattice results in excitonic excitations with substantial binding energies that are strongly coupled to the surrounding soft, polar lattice. However, the ligand environment in layered perovskites can significantly alter their optical properties due to the complex dynamic disorder of the soft perovskite lattice. Here, we infer dynamic disorder through phonon dephasing lifetimes initiated by resonant impulsive stimulated Raman photoexcitation followed by transient absorption probing for a variety of ligand substitutions. We demonstrate that vibrational relaxation in layered perovskite formed from flexible alkyl-amines as organic barriers is fast and relatively independent of the lattice temperature. Relaxation in layered perovskites spaced by aromatic amines is slower, although still fast relative to bulk inorganic lead bromide lattices, with a rate that is temperature dependent. Using molecular dynamics simulations, we explain the fast rates of relaxation by quantifying the large anharmonic coupling of the optical modes with the ligand layers and rationalize the temperature independence due to their amorphous packing. This work provides a molecular and time-domain depiction of the relaxation of nascent optical excitations and opens opportunities to understand how they couple to the complex layered perovskite lattice, elucidating design principles for optoelectronic devices.

Subsidence Characteristics in North Anhui Coal Mining Areas Using Space-Air-Ground Collaborative Observations.

To fully comprehend the patterns of land and ecological damage caused by coal mining subsidence, and to scientifically carry out ecological mine restoration and management, it is urgent to accurately grasp the information of coal mining, particularly in complex coaling areas, such as North Anhui, China. In this paper, a space-air-ground collaborative monitoring system was constructed for coal mining areas based on multi-source remote sensing data and subsidence characteristics of coaling areas were investigated in North Anhui. It was found that from 2019 to 2022, 16 new coal mining subsidence areas were found in northern Anhui, with the total area increasing by 8.1%. In terms of land use, water areas were increased by 101.9 km2 from 2012 to 2022, cultivated land was decreased by 99.3 km2, and residence land was decreased by 11.8 km2. The depth of land subsidence in the subsidence areas is divided into 307.9 km2 of light subsidence areas with a subsidence depth of less than 500 mm; 161.8 km2 of medium subsidence areas with a subsidence depth between 500 mm and 1500 mm; and 281.2 km2 of heavy subsidence areas with a subsidence depth greater than 1500 mm. The total subsidence governance area is 191.2 km2, accounting for 26.5% of the total subsidence area. From the perspective of prefecture-level cities, the governance rate reaches 51.3% in Huaibei, 10.1% in Huainan, and 13.6% in Fuyang. The total reclamation area is 68.8 km2, accounting for 34.5% of the subsidence governance area. At present, 276.1 km2 within the subsidence area has reached stable subsidence conditions, mainly distributed in the Huaibei mining area, which accounts for about 60% of the total stable subsidence area.

Ultrasound contrast-enhanced diagnosis of testicular Leydig cell tumor: A case report and literature review.

Leydig cell tumor (LCT) is a rare testicular tumor. We report a case of an elderly male patient who discovered a left testicular mass during a regular health examination four years ago. The patient did not experience any significant discomfort and opted for regular follow-up visits. During the most recent visit, we performed routine ultrasound and contrast-enhanced ultrasound (CEUS) examinations. By observing the lesion's location, echogenicity, margins, vascular distribution, as well as the rapid enhancement and slow washout characteristics on contrast-enhanced ultrasound, we arrived at a diagnosis of LCT. Subsequently, the patient underwent left inguinal orchiectomy. Postoperative pathology and immunohistochemistry confirmed the diagnosis of LCT. Additionally, we conducted a comprehensive review of LCT-related literature from PubMed and SCOPUS, summarizing the clinical features, follow-up duration, prognosis, and ultrasound characteristics associated with LCT.

Characterization of a novel SCN5A mutation associated with long QT syndrome and arrhythmogenic right ventricular cardiomyopathy in a family.

Sudden cardiac death represents a significant diagnostic challenge for forensic pathologists, particularly in inherited arrhythmia syndromes or cardiomyopathies resulting from genetic defects. Molecular autopsies can reveal the underlying molecular etiology in such cases. In this study, we investigated a family with a history of sudden cardiac death to elucidate the molecular basis responsible for sudden cardiac death. The proband underwent a comprehensive forensic examination. Family members received thorough clinical evaluations, including electrocardiogram, Holter monitoring, echocardiography, and cardiac magnetic imaging. Whole exome sequencing and genetic analysis were performed on the deceased and her parents. In addition, Western blotting and patch-clamp recordings were employed to evaluate the expression and function of the mutant protein in vitro. Forensic examination diagnosed arrhythmogenic right ventricular cardiomyopathy (ARVC) as the cause of sudden death. Genetic analysis identified a novel missense mutation in SCN5A (p.V1323L), which was assessed as likely pathogenic by the ACMG guideline. Another family member carrying the mutation manifested long QT syndrome and mild cardiac fibrosis. The cellular electrophysiological study demonstrated that the mutation resulted in an enhanced late sodium current, suggesting it was a gain-of-function mutation. This study characterizes a novel SCN5A mutation that putatively causes long QT syndrome and may contribute to the development of ARVC. Our work expands the pathogenic spectrum of SCN5A variants and underscores the importance of molecular autopsy in sudden death cases, especially in those with suspected genetic disorders.

Diazo-carboxyl Click Derivatization Enables Sensitive Analysis of Carboxylic Acid Metabolites in Biosamples.

Carboxylic acids are central metabolites in bioenergetics, signal transduction, and post-translation protein regulation. However, the quantitative analysis of carboxylic acids as an indispensable part of metabolomics is prohibitively challenging, particularly in trace amounts of biosamples. Here we report a diazo-carboxyl/hydroxylamine-ketone double click derivatization method for the sensitive analysis of hydrophilic, low-molecular-weight carboxylic acids. In general, our method renders a 5- to 2000-fold higher response in mass spectrometry along with improved chromatographic separation. With this method, we presented the near-single-cell analysis of carboxylic acid metabolites in 10 mouse egg cells before and after fertilization. Malate, fumarate, and ß-hydroxybutyrate were found to decrease after fertilization. We also monitored the isotope labeling kinetics of carboxylic acids inside adherent cells cultured in 96-well plates during drug treatment. Finally, we applied this method to plasma or serum samples (5 µL) collected from mice and humans under pathological and physiological conditions. The double click derivatization method paves a way toward single-cell metabolomics and bedside diagnostics.

Succinate dehydrogenase is essential for epigenetic and metabolic homeostasis in hearts.

A hallmark of heart failure is a metabolic switch away from fatty acids ß-oxidation (FAO) to glycolysis. Here, we show that succinate dehydrogenase (SDH) is required for maintenance of myocardial homeostasis of FAO/glycolysis. Mice with cardiomyocyte-restricted deletion of subunit b or c of SDH developed a dilated cardiomyopathy and heart failure. Hypertrophied hearts displayed a decrease in FAO, while glucose uptake and glycolysis were augmented, which was reversed by enforcing FAO fuels via a high-fat diet, which also improved heart failure of mutant mice. SDH-deficient hearts exhibited an increase in genome-wide DNA methylation associated with accumulation of succinate, a metabolite known to inhibit DNA demethylases, resulting in changes of myocardial transcriptomic landscape. Succinate induced DNA hypermethylation and depressed the expression of FAO genes in myocardium, leading to imbalanced FAO/glycolysis. Inhibition of succinate by α-ketoglutarate restored transcriptional profiles and metabolic disorders in SDH-deficient cardiomyocytes. Thus, our findings reveal the essential role for SDH in metabolic remodeling of failing hearts, and highlight the potential of therapeutic strategies to prevent cardiac dysfunction in the setting of SDH deficiency.

Analysis of the Mechanism of Action of Kushen in the Treatment of Tuberculosis Based on Network Pharmacology.

Context: Drug-resistant tuberculosis (TB), especially multidrug-resistant TB, has continued to increase and pan-drug-resistant TB and even fully drug-resistant TB have emerged, bringing great challenges to the treatment of TB. Development of new, safe, and effective antituberculosis drugs is an urgent need. Objective: The study intended to evaluate the use of the network pharmacology method to comprehensively and systematically analyze the network relationship of Kushen's main components, targets, and signaling pathways, aiming to provide new ideas and clues for an in-depth study of the mechanism of Kushen's main components in the treatment of pulmonary TB. Design: The research team performed a Network pharmacology analysis. Setting: The study took place in the Department of Respiratory and Critical Care Medicine at the Third People's Hospital of Yichang City in Yichang, Hubei, China. Outcome Measures: The research team: (1) screened Kushen's active ingredients and related targets using the Traditional Chinese Medicine System Pharmacology (TCMSP) database and analysis platform; (2) used the GeneCards database and the Online Mendelian Inheritance in Man (OMIM) database to search for disease targets, (3) connected the active ingredient's targets to the disease targets to obtain predictive targets for Kushen to act against TB, (4) used the STRING database to construct a protein-protein interaction (PPI) network map, (5) used the Database for Annotation, Visualization and Integrated Discovery (DAVID) to subject the intersecting genes to gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, and (6) used the TCMSP and Protein Data Bank (PDB) databases to dock the active ingredients with target-protein molecules. Results: The research team found 45 active ingredients for Kushen and 177 target-protein genes related to active ingredients. The PPI network map of the Kushen-TB targets and found that the top 10 targets of Kushen were: (1) mitogen-activated protein kinase 8 (MAPK8); (2) protein kinase B (AKT1); (3) MAPK1, (4) estrogen receptor 1 (ESR1), (5) rel avian reticuloendotheliosis viral oncogene homolog A (RELA), (6) interleukin-6 (IL6), (7) MYC proto-oncogene, basic helix-loop-helix (bHLH) transcription factor MYC), (8) retinoid X receptor alpha (RXRA), (9) FOS proto-oncogene activator protein 1 (AP-1) transcription factor subunit (FOS), and (10) JUN proto-oncogene AP-1 transcription factor subunit (JUN). The KEGG analysis suggested that Kushen can intervene in TB through the hypoxia-inducible factor 1 (HIF-1) signaling pathway. Conclusions: The network pharmacology analysis showed that Kushen's active ingredients can play a role in the treatment of TB through the HIF-1 signaling pathway.

A near-infrared probe for detecting and interposing amyloid beta oligomerization in early Alzheimer's disease.

BACKGROUND: The misfolding and deposition of amyloid beta (Aß) in human brain is the main hallmark of Alzheimer's disease (AD) pathology. One of the drivers of Alzheimer´s pathogenesis is the production of soluble oligomeric Aß, which could potentially serve as a biomarker of AD. METHODS: Given that the diphenylalanine (FF) at the C-terminus of Aß fragments plays a key role in inducing the AD pathology, based on the hydrophobic structure of FF, we synthesized a near-infrared BF2-dipyrrolmethane fluorescent imaging probe (NB) to detect both soluble and insoluble Aß. RESULTS: We found that NB not only binds Aß, particularly oligomeric Aß, but also interposes self-assembly of Aß through π-π interaction between NB and FF. CONCLUSION: This work holds great promise in the early detection of AD and may also provide an innovative approach to decelerate and even halt AD onset and progression.

Bromine-Enhanced Generation and Epoxidation of Ethylene in Tandem CO2 Electrolysis Towards Ethylene Oxide.

The indirect electro-epoxidation of ethylene (C2 H4 ), produced from CO2 electroreduction (CO2 R), holds immense promise for CO2 upcycling to valuable ethylene oxide (EO). However, this process currently has a mediocre Faradaic efficiency (FE) due to sluggish formation and rapid dissociation of active species, as well as reductive deactivation of Cu-based electrocatalysts during the conversion of C2 H4 to EO and CO2 to C2 H4 , respectively. Herein, we report a bromine-induced dual-enhancement strategy designed to concurrently promote both C2 H4 -to-EO and CO2 -to-C2 H4 conversions, thereby improving EO generation, using single-atom Pt on N-doped CNTs (Pt1 /NCNT) and Br- -bearing porous Cu2 O as anode and cathode electrocatalysts, respectively. Physicochemical characterizations including synchrotron X-ray absorption, operando infrared spectroscopy, and quasi in situ Raman spectroscopy/electron paramagnetic resonance with theoretical calculations reveal that the favorable Br2 /HBrO generation over Pt1 /NCNT with optimal intermediate binding facilitates C2 H4 -to-EO conversion with a high FE of 92.2 %, and concomitantly, the Br- with strong nucleophilicity protects active Cu+ species in Cu2 O effectively for improved CO2 -to-C2 H4 conversion with a FE of 66.9 % at 800 mA cm-2 , superior to those in the traditional chloride-mediated case. Consequently, a single-pass FE as high as 41.1 % for CO2 -to-EO conversion can be achieved in a tandem system.

The PROTEIN PHOSPHATASE4 Complex Promotes Transcription and Processing of Primary microRNAs in Arabidopsis.

PROTEIN PHOSPHATASE4 (PP4) is a highly conserved Ser/Thr protein phosphatase found in yeast, plants, and animals. The composition and functions of PP4 in plants are poorly understood. Here, we uncovered the complexity of PP4 composition and function in Arabidopsis (Arabidopsis thaliana) and identified the composition of one form of PP4 containing the regulatory subunit PP4R3A. We show that PP4R3A, together with one of two redundant catalytic subunit genes, PROTEIN PHOSPHATASE X (PPX)1 and PPX2, promotes the biogenesis of microRNAs (miRNAs). PP4R3A is a chromatin-associated protein that interacts with RNA polymerase II and recruits it to the promoters of miRNA-encoding (MIR) genes to promote their transcription. PP4R3A likely also promotes the cotranscriptional processing of miRNA precursors, because it recruits the microprocessor component HYPONASTIC LEAVES1 to MIR genes and to nuclear dicing bodies. Finally, we show that hundreds of introns exhibit splicing defects in pp4r3a mutants. Together, this study reveals roles for Arabidopsis PP4 in transcription and nuclear RNA metabolism.

Visible-Light-Mediated Tandem Difluoromethylation/Cyclization of Alkenyl Aldehydes toward CF2H-Substituted Chroman-4-one Derivatives.

An efficient and facile visible-light-mediated tandem difluoromethylation/cyclization of alkenyl aldehydes, with easily accessible and air-stable [Ph3PCF2H]+Br- as the difluoromethylation reagent, has been established. A range of CF2H-substituted chroman-4-one skeletons and their derivatives, such as 2,3-dihydroquinolin-4(1H)-ones, chroman, 3,4-dihydronaphthalen-1(2H)-one, 2,3-dihydrobenzofuran, and 2,3-dihydro-1H-inden-1-one, are efficiently produced in moderate to good yields with excellent chemoselectivity under mild reaction conditions.

Visible-light-mediated tandem phosphorylation/cyclization for the synthesis of phosphorylated oxindoles.

The visible-light-mediated tandem phosphorylation/cyclization of N-arylacrylamides with H-phosphine oxides has been developed for the synthesis of phosphorylated oxindoles. This efficient and facile process was useful for the construction of a C-P bond and triggered the formation of a C-C bond with good compatibility with functional groups undermild reaction conditions.

Transition-metal-free three-component coupling approach to QUINAP derivatives.

The aluminum(III) triflate catalyzed three-component coupling reaction of alkynes, amines and phosphorylated aryl aldehydes to access phosphoryl quinoline derivatives has been developed. The reaction proceeds in a simple system without the use of transition metals, ligands or additives, thus making it attractive for the fast preparation of a variety of new potential N-P bidentate ligands.

Iridoids and sesquiterpenoids from Valeriana jatamansi and their anti-influenza virus activities.

Twenty-one new iridoids, jatamansidoids A-U (1-12, 21-26, 32, 35 and 36), two new natural ones, jatamansidoids V (37) and W (38), eighteen known ones (13-20, 27-31, 33 and 34), together with three patchoulol-type sesquiterpenoids (39-41), were isolated from the roots and rhizomes of Valeriana jatamansi. Structurally, compounds 1-7 were the first examples of iridoids from V. jatamansi with unique α, ß, γ, δ-unsaturated aldehyde fragment between C-11, C-4, C-5, C-9 and C-8; compound 8 was an unprecedented iridoid derivative with a methyl group (Me-10) at C-1, rather than C-8, and its plausible biogenetic pathway was proposed in this paper; compounds 22 and 23 were the first examples of Δ4(5)-iridoids simultaneously replaced by oxygen-containing groups at C-3, C-6 and C-7; compound 24 was the first iridoid with both 6,7- and 1,10-epoxy fragments. The structures and absolute configurations of new compounds were elucidated based on extensive spectroscopic techniques and quantum chemical calculation. Furthermore, compounds 13-15 and 39-41 exhibited potent anti-influenza virus activities with H1N1 and H3N2 strains, with IC50 values of 0.21-1.48 µM.

The associations between serum high-density lipoprotein cholesterol levels and malignant behavior in pancreatic neuroendocrine neoplasms.

BACKGROUND: The role of serum high-density lipoprotein cholesterol (HDL-c) in tumorigenesis are observed in several endocrine-related cancers. However, its role in pancreatic neuroendocrine neoplasms (PNENs) has not been understood. In the current study, the relationship between HDL-c levels and malignant behavior in PNENs was explored. METHODS: One hundred ninety-seven patients with histopathology confirmed PNENs were included. PNENs were divided into three grades (G1, G2 and G3) as 2017 WHO classification based on ki67 index and mitosis count. The demographic data, clinical information, tumor morphological and pathological features (organs invasion, lymph node metastasis, vascular invasion and perineural invasion), and serum tumor biomarkers were collected. The relationships between HDL-c levels and malignant behaviors in PNENs were analyzed using logistic regression analysis. Models were also developed for the identification of high grade PNENs. RESULTS: The levels of serum HDL-c in G2/G3 tumor were significantly lower than that in G1 tumor (P = 0.031). However, no such difference was found between G3 and G1/G2. The proportions of low HDL-c (≤ 0.9 mmol/L) were higher in high-grade PNENs (G2/G3 or G3) than those in low-grade (G1 or G1/G2) (29.0 vs 15.2%, P = 0.032; 37.0 vs 20.5%, P = 0.023). The risk of G2/G3 tumors in patients with high serum HDL-c levels was decreased (odds ratio (OR) = 0.35, 95% confidence interval (CI): 0.12-0.99). Similarly, the risk of G3 PNENs increased in patients with low HDL-c levels (OR = 2.51, 95%CI:1.12-5.60). HDL-c level was also associated with a high ki67 index (> 55%) (OR = 0.10, 95%CI: 0.02-0.51) and neuroendocrine carcinoma G3 (OR = 0.21, 95%CI: 0.06-0.80). The area under the curve (AUC) of HDL-c + tumor size + age was 0.85 (95% CI: 0.79-0.91) in identifying G2/G3 PNENs, and HDL-c (> 0.9 mmol/L) + tumor size + age had an AUC of 0.77 (95% CI: 0.70-0.84) in identifying G3 PNENs. HDL-c level was associated with lymph node metastasis (OR = 0.24, 95%CI:0.08-0.99). CONCLUSION: Serum HDL-c levels were significantly associated with malignant behaviors in PNENs, in particular to tumor grade and lymph node metastasis.