Accurate prediction of drug combination risk levels based on relational graph convolutional network and multi-head attention.

BACKGROUND: Accurately identifying the risk level of drug combinations is of great significance in investigating the mechanisms of combination medication and adverse reactions. Most existing methods can only predict whether there is an interaction between two drugs, but cannot directly determine their accurate risk level. METHODS: In this study, we propose a multi-class drug combination risk prediction model named AERGCN-DDI, utilizing a relational graph convolutional network with a multi-head attention mechanism. Drug-drug interaction events with varying risk levels are modeled as a heterogeneous information graph. Attribute features of drug nodes and links are learned based on compound chemical structure information. Finally, the AERGCN-DDI model is proposed to predict drug combination risk level based on heterogenous graph neural network and multi-head attention modules. RESULTS: To evaluate the effectiveness of the proposed method, five-fold cross-validation and ablation study were conducted. Furthermore, we compared its predictive performance with baseline models and other state-of-the-art methods on two benchmark datasets. Empirical studies demonstrated the superior performances of AERGCN-DDI. CONCLUSIONS: AERGCN-DDI emerges as a valuable tool for predicting the risk levels of drug combinations, thereby aiding in clinical medication decision-making, mitigating severe drug side effects, and enhancing patient clinical prognosis.

Fine-Tuning Optoelectronic Features in Organic-Inorganic Hybrid Metal Halides: A Focus on the Phenylbutanammonium Series.

Extensive research has been dedicated to exploring the potential applications of organic-inorganic hybrid metal halides in optoelectronics. This study presents findings on three metal halides based on phenylbutanammonium (PBA). Specifically, (PBA)2MnBr4(H2O)2 and (PBA)2Sn(IV)Cl6 exhibit zero-dimensional structures with P21/c and Pnma space groups, respectively, while (PBA)2Sn(II)Br4 features a two-dimensional structure with P1̅ space group. Under UV excitation, (PBA)2MnBr4(H2O)2 exhibits double emission arising from the 4T1 → 6A1 transitions of Mn2+ in two distinct coordination environments. The emission spectrum of (PBA)2SnCl6 aligns with that of PBACl, suggesting that the luminescence originates from the organic component. The yellow emission of (PBA)2SnBr4 is attributed to the self-trapped excitons. This study introduces the PBA series of compounds, revealing that varying metal ions and halogen combinations can adjust the structural dimensions and influence optical properties. The insights gained from this work serve as a guide for the preparation of efficient white light-emitting diodes.

Fusing graph transformer with multi-aggregate GCN for enhanced drug-disease associations prediction.

BACKGROUND: Identification of potential drug-disease associations is important for both the discovery of new indications for drugs and for the reduction of unknown adverse drug reactions. Exploring the potential links between drugs and diseases is crucial for advancing biomedical research and improving healthcare. While advanced computational techniques play a vital role in revealing the connections between drugs and diseases, current research still faces challenges in the process of mining potential relationships between drugs and diseases using heterogeneous network data. RESULTS: In this study, we propose a learning framework for fusing Graph Transformer Networks and multi-aggregate graph convolutional network to learn efficient heterogenous information graph representations for drug-disease association prediction, termed WMAGT. This method extensively harnesses the capabilities of a robust graph transformer, effectively modeling the local and global interactions of nodes by integrating a graph convolutional network and a graph transformer with self-attention mechanisms in its encoder. We first integrate drug-drug, drug-disease, and disease-disease networks to construct heterogeneous information graph. Multi-aggregate graph convolutional network and graph transformer are then used in conjunction with neural collaborative filtering module to integrate information from different domains into highly effective feature representation. CONCLUSIONS: Rigorous cross-validation, ablation studies examined the robustness and effectiveness of the proposed method. Experimental results demonstrate that WMAGT outperforms other state-of-the-art methods in accurate drug-disease association prediction, which is beneficial for drug repositioning and drug safety research.

Catalytic Decarboxylative Radical Sulfinylation.

Sulfoxides are ubiquitous in both naturally and synthetically bioactive molecules. We report herein a redox-neutral and mild approach for radical sulfinylation of redox-active esters via dual photoredox and copper catalysis, furnishing a series of functionalized sulfoxides. The reaction could accommodate a range of tertiary, secondary, and primary carboxylic acids, as well as exhibit wide functional group compatibility. The chemistry features a high degree of practicality, is scalable, and allows late-stage modification of bioactive pharmaceuticals.

Luminescent hybrid halides with various centering metal cations (Zn, Cd and Pb) and diverse structures.

Organic-inorganic hybrid metal halides have been extensively studied because of their great potential in optoelectronics. Herein, we report three hybrid metal halides (Bmpip)2ZnBr4, (Bmpip)2CdBr4, and (Bmpip)8Pb11Br30 (where Bmpip+ is 1-butyl-1-methyl-piperidinium, C10H22N+). (Bmpip)2ZnBr4 and (Bmpip)2CdBr4 crystallize in the P21/c space group with zero-dimensional crystal structures with [MBr4]2- (M = Zn, Cd) tetrahedra isolated by Bmpip+. (Bmpip)8Pb11Br30 crystallizes in the triclinic space group P1̄ with one-dimensional corrugated chains constructed from face-sharing [PbBr6]4- octahedra. All of the compounds exhibit excellent ambient and thermal stability. Under UV excitation, all three compounds exhibit very broad emissions. Temperature-dependent photoluminescence measurements indicate that the broad emissions of (Bmpip)2ZnBr4 and (Bmpip)2CdBr4 can be attributed to both the organic cations and self-trapped excitons (STEs) and that the emission of (Bmpip)8Pb11Br30 is assigned to STEs. Density functional theory calculations reveal that the three compounds adopt a direct band gap. This work enriches our understanding of the structure types of hybrid metal halides while revealing their diverse emission mechanisms.

High-Efficiency Intrinsic Yellow-Orange Emission in Hybrid Indium Bromide with Double Octahedral Configuration.

Zero-dimensional (0D) In-based organic-inorganic metal halides (OIMHs) have received growing interest in recent years as promising luminescent materials. However, the high efficiencies of 0D In-based OIMHs are all dependent on Sb doping in the existing literature. Here, we report a novel 0D In-based OIMH (C10H22N2)2In2Br10, which exhibits intrinsic broadband emission (610 nm), and the photoluminescence quantum yield (PLQY) can reach 70% without Sb doping. (C10H22N2)2In2Br10 shows a typical 0D structure with three different In-Br polyhedra (two octahedra and one tetrahedron) separated by large organic cations. Based on the optical property measurements and theoretical calculations, we demonstrate that (C10H22N2)2In2Br10 is an indirect semiconductor with a band gap of 3.74 eV, and the In-Br inorganic moiety is primarily responsible for the intense emission of (C10H22N2)2In2Br10. Interestingly, the unique double octahedral configuration in (C10H22N2)2In2Br10 may enhance the structural distortion and stimulate the self-trapped excitons (STEs), leading to the related high PLQY. Our work provides a novel 0D In-based OIMH with high-efficiency intrinsic emission, which is helpful for understanding the structure-PL relationships of hybrid halides.

Improving the Chemical Stability of Narrow-Band Green-Emitting Manganese(II) Hybrid by Zn-Doping.

Hybrid tetrahedral Mn(II)-based halides show great potential for narrow-band green emitters, which could be applied in the liquid crystal display field. However, the strategy to improve the chemical stability of tetrahedral Mn hybrids has not been fully investigated. Here, we demonstrate that Zn doping can be an effective route to significantly improve the stability of tetrahedral Mn hybrids under air conditions without compromising the luminous efficiency. A new bromide (ABI)2MnBr4 (ABI = 2-aminobenzimidazole) is synthesized, which exhibits a typical zero-dimensional structure with isolated [MnBr4]2- tetrahedra in the P1̅ space group. Under 450 nm excitation, a narrow-band green-emitting peak at 516 nm is observed with a full width at half maximum of 42 nm. It is indicated that spontaneous phase transition from the tetrahedral to octahedral motif occurs in this Mn hybrid driven by humidity, combined with the emission color change from green to red. Interestingly, this phase transition could be strongly suppressed by Zn doping with a very low doping amount (5%), leading to the significantly improved chemical stability of (ABI)2MnBr4 without reducing the photoluminescence quantum yield. Our work provides a simple and feasible strategy to enhance the chemical stability of the green-emitting (ABI)2MnBr4, and it may also be applicable for other tetrahedral Mn-based hybrids.

Effect of Arthroscopic Acromioplasty Combined with Rotator Cuff Repair in the Treatment of Aged Patients with Full-Thickness Rotator Cuff Tear and Rotator Cuff Injury.

Full-thickness rotator cuff tear and rotator cuff injury are frequently occurring diseases and widely exist in the social population. Surgical repair is the most effective treatment for rotator cuff tears and injuries. With the continuous development of arthroscopy, more and more surgeons choose arthroscopic acromioplasty plus rotator cuff repair for the treatment of rotator cuff injury. However, previously published systematic reviews or meta-analyses still cast doubt on the efficacy of such concomitant procedures for postoperative patient function and pain recovery. In this study, we analyzed the effects of parameters such as shoulder function and acromion morphology on aged patients with full-thickness rotator cuff tear combined with rotator cuff injury treated with arthroscopic acromion plasty and rotator cuff repair. The results showed that arthroscopic acromion plasty and rotator cuff repair helped to promote the joint function recovery of the aged patients with full-thickness rotator cuff tear combined with rotator cuff injury and alleviate the pain of the patients. Compared with simple rotator cuff repair, this technique can increase the postoperative AT and reduce the ACEA and to some extent reduce the risk of postoperative rotator cuff reinjury, which is worthy of promotion.

Photoluminescent Properties of Two-Dimensional Manganese(II)-Based Perovskites with Different-Length Arylamine Cations.

The participation of organic cations plays an important role in tuning broad-spectra emissions. Herein, we synthesized a series of Mn(II)-based two-dimensional (2D) halide perovskites with arylamine cations of different lengths having the general formula (C6H5(CH2)xNH3)2MnCl4 (x = 1-4), with the x = 4 compound reported here for the first time. With the increase in the -(CH2)- in organic cations, the distance between adjacent inorganic layers increases, causing the title compounds to exhibit different structural distortions. As the Mn-Cl-Mn angular distortion increases, the experimental optical band gaps of the title compounds increase correspondingly. When the angle distortion between the octahedrons of the compounds is similar, the band gaps may also be affected by the distortion of the octahedron itself (the bond-length distortion of 2 is greater than that of 4). Under UV-light irradiation at 298 K, all of the compounds exhibit two emission peaks centered at 480-505 and 610 nm, corresponding to the organic-cation emission and the 4T1(G) to 6A1(S) radiative transition of Mn2+ ions, respectively. Among these title compounds, (PPA)2MnCl4 [(PPA)+ = C6H5(CH2)3NH3+] exhibits the strongest photoluminescence (PL). The study of the title compounds contributes to an in-depth understanding of the relationship between the structural distortion and optical properties of 2D Mn(II)-based perovskite materials.

Small Organic Molecular-Based Hybrid Halides with High Photoluminescence Quenching Temperature.

Organic-inorganic metal halides (OIMHs) exhibit excellent photoelectric properties; however, their high-temperature light-emission stability requires further improvement. Here, we report three isostructural OIMHs (C2H8N)4InCl7, (C2H8N)4SbCl7, and (C2H8N)4SbBr7 (C2H8N+ = dimethylammonium). They are all crystallized in the P21212 space group with a zero-dimensional (0D) structure, with orange-red photoluminescence (PL) under 365 nm UV excitation. Among them, (C2H8N)4InCl7 exhibits the strongest PL with a photoluminescence quantum yield (PLQY) of 13.9% at room temperature. Optical property measurements and density functional theory unveil that the luminescence of (C2H8N)4InCl7 at 405 and 620 nm is due to free exciton and self-trapped exciton emission, respectively. It is worth noting that (C2H8N)4InCl7 shows a high PL quenching temperature, maintaining 50% of its room-temperature PL intensity at 425 K, which is rare in OIHMs. This is much higher than the application temperature of phosphors in practical solid-state lighting applications (363-383 K). In this temperature range, the luminous intensity of (C2H8N)4InCl7 exceeds 60% of that at room temperature. The high PL quenching temperature observed in (C2H8N)4InCl7 indicates the potential of OIMHs for applications in phosphor-converted light-emitting diodes.

MMP12 knockout prevents weight and muscle loss in tumor-bearing mice.

BACKGROUND: Colorectal cancer is a malignant gastrointestinal cancer, in which some advanced patients would develop cancer cachexia (CAC). CAC is defined as a multi-factorial syndrome characterized by weight loss and muscle loss (with or without fat mass), leading to progressive dysfunction, thereby increasing morbidity and mortality. ApcMin/+ mice develop spontaneous intestinal adenoma, which provides an established model of colorectal cancer for CAC study. Upon studying the ApcMin/+ mouse model, we observed a marked decrease in weight gain beginning around week 15. Such a reduction in weight gain was rescued when ApcMin/+ mice were crossed with MMP12-/- mice, indicating that MMP12 has a role in age-related ApcMin/+-associated weight loss. As a control, the weight of MMP12-/- mice on a weekly basis, their weight were not significantly different from those of WT mice. METHODS: ApcMin/+; MMP12-/- mice were obtained by crossing ApcMin/+ mice with MMP12 knockout (MMP12 -/-) mice. Histological scores were assessed using hematoxylin-eosin (H&E) staining. MMP12 expression was confirmed by immunohistochemistry and immunofluorescence staining. ELISA, protein microarrays and quantitative Polymerase Chain Reaction (qPCR) were used to investigate whether tumor could up-regulate IL-6. Cell-based assays and western blot were used to verify the regulatory relationship between IL-6 and MMP12. Fluorescence intensity was measured to determine whether MMP12 is associated with insulin and insulin-like growth factor 1 (IGF-1) in vitro. MMP12 inhibitors were used to explore whether MMP12 could affect the body weight of ApcMin/+ mice. RESULTS: MMP12 knockout led to weight gain and expansion of muscle fiber cross-sectional area (all mice had C57BL/6 background) in ApcMin/+ mice, while inhibiting MMP12 could suppress weight loss in ApcMin/+ mice. MMP12 was up-regulated in muscle tissues and peritoneal macrophages of ApcMin/+ mice. IL-6 in tumor cells and colorectal cancer patients is up-regulation. IL-6 stimulated MMP12 secretion of macrophage. CONCLUSIONS: MMP12 is essential for controlling body weight of Apc Min/+ mice. Our study shows that it exists the crosstalk between cancer cells and macrophages in muscle tissues that tumor cells secrete IL-6 inducing macrophages to up-regulate MMP12. This study may provide a new perspective of MMP12 in the treatment for weight loss induced by CAC.

Copper-Catalyzed N-Directed Distal C(sp3)-H Sulfonylation and Thiolation with Sulfinate Salts.

We herein report a selective and catalytic C(sp3)-H functionalization approach to access amines bearing organo-sulfonyl and organo-thiol groups. This reaction proceeds through a cascade process of N-radical formation, alkyl radical formation via 1,5-HAT, and C-S bond formation, thereby offering a series of functionalized amines. This method could enable primary, secondary, and tertiary C(sp3)-H sulfonylation and thiolation and also exhibits good functional group tolerance.

A morpholino hydrazone-based lysosome-targeting fluorescent probe with fast response and high sensitivity for imaging peroxynitrite in living cells.

Peroxynitrite (ONOO-) plays important roles in many pathophysiological processes and its subcellular detection draws increasing attention. In this study, we designed and prepared a novel lysosome-targetable fluorescent probe (E)-2-(benzo[d]thiazol-2- yl)-4-methyl-6-((morpholinoimino)methyl)phenol (BMP) for selective detection of ONOO- in living systems by incorporating a reactive morpholino hydrazone as new ONOO- response site into a benzothiazole derivative as fluorophore. After reaction with ONOO-, an obvious fluorescence increase (83-fold) was observed accompanied with distinct dual colorimetric and fluorescence changes. Probe BMP displayed the merits of fast response (<3 s), ultrasensitivity (LOD = 6 nM) and high selectivity towards ONOO- over other physiological species including ROS/RNS. Most importantly, the probe was capable of imaging ONOO- in lysosomes of living cells with good cell permeation and negligible cytotoxicity. Therefore, this research provides an effective tool to study the functions of ONOO- in lysosomes.

Efficiency-Tunable Single-Component White-Light Emission Realized in Hybrid Halides Through Metal Co-Occupation.

Organic-inorganic hybrid metal halides have attracted widespread attention as emerging optoelectronic materials, especially in solid-state lighting, where they can be used as single-component white-light phosphors for white light-emitting diodes. Herein, we have successfully synthesized a zero-dimensional (0D) organic-inorganic hybrid mixed-metal halide (Bmpip)2PbxSn1-xBr4 (0 < x < 1, Bmpip+ = 1-butyl-1-methyl-piperidinium, C10H22N+) that crystallizes in a monoclinic system in the C2/c space group. Pb2+ and Sn2+ form a four-coordinate seesaw structure separated by organic cations forming a 0D structure. For different excitation wavelengths, (Bmpip)2PbxSn1-xBr4 (0 < x < 1) exhibits double-peaked emission at 470 and 670 nm. The emission color of (Bmpip)2PbxSn1-xBr4 can be easily tuned from orange-red to blue by adjusting the Pb/Sn molar ratio or excitation wavelength. Representatively, (Bmpip)2Pb0.16Sn0.84Br4 exhibits approximately white-light emission with high photoluminescence quantum yield up to 39%. Interestingly, the color of (Bmpip)2PbxSn1-xBr4 can also be easily tuned by temperature, promising its potential for application in temperature measurement and indication. Phosphor-converted light-emitting diodes are fabricated by combining (Bmpip)2PbxSn1-xBr4 and 365 nm near-UV LED chips and exhibit high-quality light output.

Simvastatin inhibits POVPC-mediated induction of endothelial-to-mesenchymal cell transition.

Endothelial-to-mesenchymal transition (EndMT), the process by which an endothelial cell (EC) undergoes a series of molecular events that result in a mesenchymal cell phenotype, plays an important role in atherosclerosis. 1-Palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), derived from the oxidation of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine, is a proinflammatory lipid found in atherosclerotic lesions. Whether POVPC promotes EndMT and how simvastatin influences POVPC-mediated EndMT remains unclear. Here, we treated human umbilical vein ECs with POVPC, simvastatin, or both, and determined their effect on EC viability, morphology, tube formation, proliferation, and generation of NO and superoxide anion (O2•-). Expression of specific endothelial and mesenchymal markers was detected by immunofluorescence and immunoblotting. POVPC did not affect EC viability but altered cellular morphology from cobblestone-like ECs to a spindle-like mesenchymal cell morphology. POVPC increased O2- generation and expression of alpha-smooth muscle actin, vimentin, Snail-1, Twist-1, transforming growth factor-beta (TGF-ß), TGF-ß receptor II, p-Smad2/3, and Smad2/3. POVPC also decreased NO production and expression of CD31 and endothelial NO synthase. Simvastatin inhibited POVPC-mediated effects on cellular morphology, production of O2•- and NO, and expression of specific endothelial and mesenchymal markers. These data demonstrate that POVPC induces EndMT by increasing oxidative stress, which stimulates TGF-ß/Smad signaling, leading to Snail-1 and Twist-1 activation. Simvastatin inhibited POVPC-induced EndMT by decreasing oxidative stress, suppressing TGF-ß/Smad signaling, and inactivating Snail-1 and Twist-1. Our findings reveal a novel mechanism of atherosclerosis that can be inhibited by simvastatin.

Axin 1 knockdown inhibits osteoblastic apoptosis induced by Porphyromonas gingivalis lipopolysaccharide.

BACKGROUND: Porphyromonas gingivalis (Pg) is one of the pathogenic bacteria that cause periodontal diseases, lipopolysaccharide (LPS) is the key factor that triggers alveolar bone absorption. This study explored the action of Axin 1 on Pg-LPS-induced osteoblasts injury, so as to search a possible treatment for periodontal diseases. METHODS: Rat osteoblasts were dealt with Pg-LPS and Axin 1 knockdown alone or in combination. The effect of Pg-LPS and Axin 1 on osteoblast viability and apoptosis were detected by Cell Counting Kit-8 and flow cytometry. The expressions of alkaline phosphatase (ALP) and Axin 1 in processed osteoblasts were measured by western blot (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) assays. Furthermore, the role of Axin 1 knockdown in the levels of inflammatory cytokines and apoptosis-related proteins were also determined. RESULTS: Pg-LPS inhibited the viability of osteoblasts and promote apoptosis with concentration and time dependence. ALP expression in Pg-LPS-treated osteoblasts was reduced, while Axin 1 expression was increased. On the one hand, Axin 1 knockdown reversed the Pg-LPS-induced reduction of cell activity and pro-apoptosis effect. On the other hand, Axin 1 knockdown not only improved the ALP activity of Pg-LPS-treated cells, but also reduced the elevation of inflammatory cytokines (TNF-α, IL-1ß and IL-6) caused by Pg-LPS. Moreover, Pg-LPS increased the expressions of cleaved Caspase-3 and Bax, and inhibited Bcl-2 expressed, which was rescued by Axin 1 knockdown. CONCLUSION: Axin 1 knockdown inhibited Pg-LPS-induced osteoblastic apoptosis by regulating the levels of inflammatory cytokines, which may be helpful for the treatment of periodontal diseases.

Synthesis and Evaluation of the Anticonvulsant Activities of 4-(2-(Alkylthio)benzo[d]oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-ones.

In this study, a novel series of 4-(2-(alkylthio)benzo[d]oxazol-5-yl)-2,4-dihydro-3H-1,2,4-triazol-3-ones (4a-m) was designed and synthesized. The anticonvulsant activities of these compounds were evaluated by using the maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) seizure models in mice. The neurotoxicity of these compounds was evaluated using the rotarod neurotoxicity test. The majority of compounds showed anti-MES activities at 100 or 300 mg/kg. Compound 4g was considered to be the most promising, based on its potency against MES- and PTZ-induced seizures with ED50 values of 23.7 and 18.9 mg/kg, respectively. The TD50 value of 4g was 284.0 mg/kg, which resulted in a higher protective index (PI = TD50/ED50) value than that of carbamazepine and valproate. In an ELISA test, compound 4g significantly increased the γ-aminobutyric acid (GABA) content in mouse brain. In addition, pretreatment with thiosemicarbazide (an inhibitor of the GABA synthesizing enzyme) significantly decreased the activity of 4g in the MES model, which suggests that the mechanism through which compound 4g elicits its anticonvulsive action is at least in part through increasing the GABA level in the brain.

The oxidized phospholipid POVPC impairs endothelial function and vasodilation via uncoupling endothelial nitric oxide synthase.

Endothelial dysfunction is an early stage of atherosclerosis. We recently have shown that 25-hydroxycholesterol found in atherosclerotic lesions could impair endothelial function and vasodilation by uncoupling and inhibiting endothelial nitric oxide synthase (eNOS). 1-Palmitoyl-2-(5-oxovaleroyl)-sn-glycero-3-phosphocholine (POVPC), the oxidation product of oxidized low-density lipoprotein, is another proinflammatory lipid and has also been found in atherosclerotic lesions. However, whether POVPC promotes atherosclerosis like 25-hydroxycholesterol remains unclear. The purpose of this study was to explore the effects of POVPC on endothelial function and vasodilation. Human umbilical vein endothelial cells (HUVECs) were incubated with POVPC. Endothelial cell proliferation, migration and tube formation were measured. Nitric oxide (NO) production and superoxide anion generation (O2-) were determined. The expression and phosphorylation of endothelial nitric oxide synthase (eNOS), AKT, PKC-ßII and P70S6K as well as the association of eNOS and heat shock protein 90 (HSP90) were detected by immunoblotting and immunoprecipitation. Endothelial cell apoptosis was monitored by TUNEL staining. The expression of Bcl-2, Bax, and Cleaved Caspase 3 were detected by immunoblotting. Finally, aortic ring from C57BL6 mice were isolated and treated with POVPC and the endothelium-dependent vasodilation was evaluated. POVPC significantly inhibited HUVECs proliferation, migration, tube formation, decreased NO production but increased O2- generation. POVPC inhibited the phosphorylation of Akt and eNOS at Ser1177, increased activation of PKC-ßII, P70S6K and the phosphorylation of eNOS at Thr495, reduced the association of HSP90 with eNOS. Meanwhile, POVPC induced endothelial cell apoptosis by inhibiting Bcl-2 expression, increasing Bax and cleaved caspase-3 expressions as well as caspase-3 activity and impaired endothelium-dependent vasodilation. These data demonstrated that POVPC impaired endothelial function by uncoupling and inhibiting eNOS as well as by inducing endothelial cell apoptosis. Therefore, POVPC may play an important role in the development of atherosclerosis and may be considered as a potential therapeutic target for atherosclerosis.

Deterioration of insulin release rate response to glucose during oral glucose tolerance test is associated with an increased risk of incident diabetes in normal glucose tolerance subjects.

ß-Cell dedifferentiation, characterized by loss of glucose sensitivity (ß-cell glucose sensitivity [ßCGS]), has been reported to play an important role in the development of type 2 diabetes (T2D). Traditionally, ßCGS was derived from C-peptide-based method. However, C-peptide was not routinely examined in normal subjects and diabetes never treated with insulin. Thus, the aim of the study was to evaluate the use of insulin in oral glucose tolerance test (OGTT) in estimation of ß-cell glucose response ability. A total of 1,599 subjects including normal glucose tolerance (NGT), impaired glucose tolerance (IGT) and T2D were included in the study. A subgroup of NGT subjects (n = 591) were followed up for an average duration of 56.88 ± 20.76 months. Insulin release rate (IRRINS ) in the function of glucose (IRRINS response to glucose [IRRG]) during OGTT was compared with ßCGS. Both ßCGS derived from C-peptide by deconvolution approach and IRRG by insulin release progressively declined from NGT to IGT and T2D. Both ßCGS and IRRG were associated with deposit of first-phase insulin secretion (DI1st ). After 56.88 ± 20.76 months, 32 (5.41%) NGT subjects had developed T2D. NGT subjects who progressed to diabetes after follow-up had lower IRRG and DI1st levels than those who did not (P < 0.01). Furthermore, multiple logistic regression analyses showed that decreased IRRG was a significant independent risk predictor for future diabetes after adjustment of age, body mass index (BMI), homeostasis model assessment (HOMA)-insulin resistance, DI1st and family history. NGT subjects with decreased IRRG during OGTT had defective early insulin secretion and were at higher risk of developing diabetes. IRRG could be a useful T2D predictor in NGT subjects. © 2017 IUBMB Life, 69(9):756-766, 2017.