Triglyceride-glucose index is associated with severe obstructive coronary artery disease and atherosclerotic target lesion failure among young adults.

BACKGROUND: Early diagnosis and treatment effectiveness of early-onset coronary artery disease (EOCAD) are crucial, and non-invasive predictive biomarkers are needed for young adults. We aimed to evaluate the usefulness of the triglyceride-glucose (TyG) index, a novel marker of insulin resistance, in identifying young CAD patients and predicting their risk of developing target lesion failure (TLF). METHODS: We recruited EOCAD patients (luminal narrowing ≥ 70%) and controls free from CAD (luminal narrowing < 30%), both aged 45 years or younger, from 38 hospitals in China between 2017 and 2020. EOCAD patients who underwent successful percutaneous coronary intervention were followed for incident TLF. TyG index was defined as Ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2]. We used logistic regression and Cox proportional hazards modeling to evaluate the association of TyG index with prevalent EOCAD and incident TLF, respectively. The discriminatory ability of TyG index was assessed by the area under the receiver-operating characteristic curve (AUC). RESULTS: Among the included 1513 EOCAD patients (39.6 ± 4.4 years, 95.4% male) and 1513 age-matched controls (39.0 ± 4.4 years, 46.4% male), TyG index was positively associated with the prevalence of EOCAD (adjusted odds ratio: 1.40, 95% confidence interval [CI] 1.23-1.60, per standard deviation [SD] increase in TyG index). The addition of TyG index to an empirical risk model provided an improvement in diagnostic ability for EOCAD, with a net reclassification improvement of 0.10 (95% CI 0.03-0.17, p = 0.005). During a medium of 33 month (IQR: 31-34 months) follow-up, 43 (3.3%) patients experienced TLF. Multivariate Cox regression model revealed that TyG index was an independent risk factor for TLF (adjusted hazard ratio [HR]: 2.410, 95% CI 1.07-5.42 comparing the top to bottom TyG index tertile groups; HR: 1.30, 95% CI 1.01-1.73, per SD increase in TyG index). Compared with a model of conventional risk factors alone, the addition of the TyG index modestly improved the AUC (0.722-0.734, p = 0.04) to predict TLF. CONCLUSIONS: TyG index is positively associated with prevalent EOCAD and incident TLF. TyG index appeared to be a valuable component of future efforts to improve CAD risk stratification and TLF outcome prediction among young adults.

VPT-like genes modulate Rhizobium-legume symbiosis and phosphorus adaptation.

Although vacuolar phosphate transporters (VPTs) are essential for plant phosphorus adaptation, their role in Rhizobium-legume symbiosis is unclear. In this study, homologous genes of VPT1 (MtVPTs) were identified in Medicago truncatula to assess their roles in Rhizobium-legume symbiosis and phosphorus adaptation. MtVPT2 and MtVPT3 mainly positively responded to low and high phosphate, respectively. However, both mtvpt2 and mtvpt3 mutants displayed shoot phenotypes with high phosphate sensitivity and low phosphate tolerance. The root-to-shoot phosphate transfer efficiency was significantly enhanced in mtvpt3 but weakened in mtvpt2, accompanied by lower and higher root cytosolic inorganic phosphate (Pi) concentration, respectively. Low phosphate induced MtVPT2 and MtVPT3 expressions in nodules. MtVPT2 and MtVPT3 mutations markedly reduced the nodule number and nitrogenase activity under different phosphate conditions. Cytosolic Pi concentration in nodules was significantly lower in mtvpt2 and mtvpt3 than in the wildtype, especially in tissues near the base of nodules, probably due to inhibition of long-distance Pi transport and cytosolic Pi supply. Also, mtvpt2 and mtvpt3 could not maintain a stable cytosolic Pi level in the nodule fixation zone as the wildtype under low phosphate stress. These findings show that MtVPT2 and MtVPT3 modulate phosphorus adaptation and rhizobia-legume symbiosis, possibly by regulating long-distance Pi transport.

In situ assessment of statins' effect on autophagic activity in zebrafish larvae cardiomyocytes.

Improving the survival rate of cardiomyocytes is the key point to treat most of the heart diseases, and targeting autophagy is a potential advanced therapeutic approach. Monitoring autophagic activity in cardiomyocytes in situ will be useful for studying autophagy-related heart disease and screening autophagy-modulating drugs. Zebrafish, Danio rerio, has been proven as an animal model for studying heart diseases in situ. Taken the advantage of zebrafish, especially the imaging of intact animals, here we generated two stable transgenic zebrafish lines that specifically expressed EGFP-map1lc3b or mRFP-EGFP-map1lc3b in cardiomyocytes under the promoter of myosin light chain 7. We first used a few known autophagy-modulating drugs to confirm their usefulness. By quantifying the density of autophagosomes and autolysosomes, autophagy inducers and inhibitors showed their regulatory functions, which were consistent with previous studies. With the two lines, we then found a significant increase in the density of autophagosomes but not autolysosomes in zebrafish cardiomyocytes at the early developmental stages, indicating the involvement of autophagy in early heart development. To prove their applicability, we also tested five clinical statins by the two lines. And we found that statins did not change the density of autophagosomes but reduced the density of autolysosomes in cardiomyocytes, implying their regulation in autophagic flux. Our study provides novel animal models for monitoring autophagic activity in cardiomyocytes in situ, which could be used to study autophagy-related cardiomyopathy and drug screening.

Systematic Analysis of Neurotransmitter Receptors in Human Breast Cancer Reveals a Strong Association With Outcome and Uncovers HTR6 as a Survival-Associated Gene Potentially Regulating the Immune Microenvironment.

Many epidemiological reports have indicated an increase in the incidence of breast cancer among psychotic patients, suggesting that the targets of antipsychotics, neurotransmitter receptors, may have a role in tumorigenesis. However, the functions of neurotransmitter receptors in cancer are barely known. Here, we analyzed 44 neurotransmitter receptors in breast cancer and revealed that the expression of 34 receptors was positively correlated with relapse-free survival rates (RFS) of patients using the public database (n = 3951). Among all these receptors, we revealed decreased expression of HTR6 in human advanced breast cancer versus tumors in situ using our original data (n = 44). After a pan-cancer analysis including 22 cancers (n = 11262), we disclosed that HTR6 was expressed in 12 tumors and uncovered its influence on survival in seven tumors. Using multi-omics datasets from Linkedomics, we revealed a potential regulatory role of HTR6 in MAPK, JUN, and leukocyte-differentiation pathways through enriching 294 co-expressed phosphorylated proteins of HTR6. Furthermore, we proclaimed a close association of HTR6 expression with the immune microenvironment. Finally, we uncovered two possible reasons for HTR6 down-regulation in breast cancer, including deep deletion in the genome and the up-regulation of FOXA1 in breast cancer, which was a potential negatively regulatory transcription factor of HTR6. Taken together, we revealed a new function of neurotransmitter receptors in breast cancer and identified HTR6 as a survival-related gene potentially regulating the immune microenvironment. The findings in our study would improve our understanding of the pathogenesis of breast cancer and provided a theoretical basis for personalized medication in psychotic patients.

PTP70-2, a novel polysaccharide from Polygala tenuifolia, prevents neuroinflammation and protects neurons by suppressing the TLR4-mediated MyD88/NF-κB signaling pathway.

PTP70-2, a novel polysaccharide isolated from Polygala tenuifolia in our previous publication, exhibits potential anti-inflammatory effects. Here, we investigate the mechanisms underlying these effects and the neuroprotective activity of PTP70-2 in lipopolysaccharide (LPS)-damaged BV2 microglial cells and neuroinflammation-injured primary cortical neurons. The results suggest that PTP70-2 dramatically reduces the LPS-stimulated inflammatory cytokines overexpression, as well as down-regulates the levels of TLR4-, MyD88-, and NF-κB-related proteins. The effect of PTP70-2 in down-regulation of proinflammatory cytokines and downstream proteins implicated in MyD88 and NF-κB signaling is related to the TLR4 pathway. Furthermore, this effect is enhanced by the co-incubation of BV2 cells with PTP70-2 and TAK242, a TLR4 inhibitor, before exposure to LPS. Importantly, PTP70-2 prevents neuroinflammation-induced neurotoxicity by mitigating ROS overproduction and MMP dissipation. Overall, the PTP70-2's anti-neuroinflammation and neuroprotection are involved to the modulation of the TLR4-mediated MyD88/NF-κB signaling pathway.