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Objective: The Estimated Glucose Disposal Rate (eGDR) serves as a surrogate marker for insulin resistance, with numerous studies highlighting its significant prognostic value. This paper aims to analyze the impact of eGDR on cardiovascular and all-cause mortality across different glycemic metabolic statuses, including normal fasting glucose (NFG), prediabetes, and diabetes. Methods: This study included 46,016 American adults who underwent health examinations as part of the National Health and Nutrition Examination Survey from 1999 to 2018. Multivariable Cox regression was employed to explore the relationships between eGDR and mortality rates under varying glycemic states. Additionally, Kaplan-Meier curves were used to compare the cumulative incidence of cardiovascular and all-cause mortality across different metabolic statuses. Finally, the predictive value of eGDR for mortality was assessed using receiver operating characteristic curves. Results: During an average follow-up of 115 months, a total of 6,906 (15.01%) participants experienced all-cause mortality, with 1,798 (3.91%) deaths attributed to cardiovascular causes. Kaplan-Meier analysis revealed that higher eGDR levels were associated with gradually reduced mortality rates. After adjusting for confounders, elevated eGDR levels were protective against both cardiovascular and all-cause mortality; the protective effect was notably stronger for cardiovascular mortality [Cardiovascular mortality hazard ratio: 0.92; All-cause mortality hazard ratio: 0.94]. Further interaction tests indicated that glycemic status significantly modified the protective effect of eGDR (P -interaction<0.0001); specifically, high eGDR conferred stronger protection against cardiovascular and all-cause mortality in individuals with NFG and prediabetes compared to those with diabetes. Receiver operating characteristic analysis suggested that eGDR had superior predictive value for mortality in the NFG and prediabetic populations compared to the diabetic group. Conclusion: eGDR is a straightforward surrogate for insulin resistance, acting as a protective factor against cardiovascular and all-cause mortality in American adults, with glycemic status modifying this protective effect. Specifically, high eGDR levels offer stronger protection in individuals with NFG and prediabetes compared to those with diabetes; moreover, eGDR appears to be more suitable for predicting mortality events in the NFG and prediabetic populations. [ABSTRACT FROM AUTHOR]

Esophageal cancer (EC) is one of the most common highly malignant tumors of the digestive system, with a poor prognosis under current treatment regimens. Nucleolin (NCL) is overexpressed in many tumors, and drugs specifically targeting NCL may offer a promising strategy for treating esophageal cancer. Here, we designed and prepared a novel aptamer-conjugated drug targeting NCL by AS1411 aptamer-human serum albumin (HSA)-the apoprotein of lidamycin (LDP)-active enediyne chromophore (AE), in order to achieve targeted treatment of esophageal cancer. The experimental results revealed that AS1411-HSA-LDP effectively binds to esophageal cancer cells and could be efficiently internalized by esophageal cancer cells. In the KYSE520 xenograft tumor nude mouse model, AS1411-HSA-LDP could be targeted and enriched in the tumor location for a long time. AS1411-HSA-LDP-AE exhibited a strong cell-killing activity in esophageal cancer cells, inhibited cell migration and invasion, and induced cell apoptosis. The animal studies confirmed that AS1411-HSA-LDP-AE exhibited a strong anti-tumor effect. These findings suggested that the novel NCL-targeting aptamer-drug conjugate constructed based on lidamycin exhibited a strong anti-tumor effect, providing a promising strategy for the targeted treatment of esophageal cancer. [ABSTRACT FROM AUTHOR]

Objective: The deterioration of acute decompensated heart failure (ADHF) is associated with abnormal activation of inflammatory pathways. This study aims to evaluate the impact and predictive value of a novel inflammatory marker, the systemic inflammation response index (SIRI), on short-term adverse outcomes in ADHF patients. Methods: This retrospective cohort study included 1,448 ADHF patients from Jiangxi Provincial People's Hospital between 2019-2022. SIRI was calculated using the formula: (neutrophil count × monocyte count)/lymphocyte count. In the correlation analysis, the study outcome was the 30-day mortality in patients with ADHF. Cox regression analysis and receiver operating characteristic curves were employed to investigate the risk assessment and predictive value of the SIRI for 30-day mortality in ADHF patients. Finally, we also exploratively assessed the mediation effect of nutritional factors (albumin: Alb, total cholesterol: TC, and lymphocyte count) on the association between SIRI and 30-day mortality in ADHF patients. Results: During the 30-day follow-up, 53 deaths were recorded. Mortality rates across SIRI tertiles were 0.62%, 2.07%, and 8.28%, respectively. There was a significant linear positive correlation between SIRI and 30-day mortality in ADHF patients (HR: 1.21; P for non-linearity = 0.113). Additionally, compared to ADHF patients with low SIRI, those with high SIRI had a 685% increased risk of 30-day mortality (HR: 7.85). Furthermore, receiver operating characteristic curve analysis demonstrated that SIRI significantly improved the predictive value for 30-day mortality in ADHF patients compared to neutrophil count, monocyte count, and lymphocyte count alone (AUC: neutrophil count 0.7633, monocyte count 0.6835, lymphocyte count 0.7356, SIRI 0.8237; all DeLong P <0.05). Mediation analyses indicated that, except for lymphocyte count, both Alb and TC had significant indirect effects on the SIRI-related 30-day mortality in ADHF patients; Specifically, Alb accounted for approximately 24.46% of the mediation effect, while TC accounted for approximately 13.35%. Conclusion: This cohort study based on a Southern Chinese population demonstrates a significant linear positive correlation between SIRI and 30-day mortality in ADHF patients, highlighting its substantial predictive value. Incorporating SIRI into the monitoring regimen of ADHF patients may be crucial for preventing further disease progression. [ABSTRACT FROM AUTHOR]

Parkinson's disease (PD) is a chronic neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra compacta, which may result from mitochondrial dysfunction and oxidative stress. Isorhamnetin (Iso) has important antioxidative stress and antiapoptotic effects, this study investigated the effects of Iso on PD in vitro and its underlying mechanisms using a model of 6-hydroxydopamine (6-OHDA)-induced SH-SY5Y cell damage. The results showed that Iso significantly ameliorated 6-OHDA-induced SH-SY5Y cell injury, including decreased cell viability, increased apoptosis and senescence, and oxidative stress injury. Senescence-associated β-galactosidase (SA-β) staining, Western blot (WB), and immunofluorescence suggested that Iso significantly decreased the number of SA-β+ cells and the levels of senescence-associated proteins p21 and p16, and enhanced tyrosine hydroxylase level. Iso markedly reduced the number of apoptotic cells and the levels of cleaved caspase-3 and BAX, as detected by CCK-8, flow cytometry, and WB. The results of DCFH-DA, JC-1 staining, and the measurement of malondialdehyde (MDA) and superoxide dismutase (SOD) content indicated that Iso elevated reactive oxygen species (ROS) generation and mitochondrial membrane potential, lowered MDA content and raised SOD level in the 6-OHDA group. In-depth investigation revealed that Iso activated the AKT/mTOR signal via reducing the expression level of Fos-like antigen (FOSL1), which further exerted the protective effect in SH-SY5Y cells. Overexpression of FOSL1 attenuated the effect of Iso by inhibiting the AKT/mTOR signaling pathway. Taken together, Iso protects against senescence, apoptotic, and oxidative stress injury by targeting FOSL1 to activate the AKT/mTOR signaling pathway in 6-OHDA-induced SH-SY5Y cells, which may provide new insights for PD treatment. NEW & NOTEWORTHY: Isorhamnetin (Iso) ameliorated neuronal activity damage, senescence, apoptosis, and oxidative stress injury in 6-hydroxydopamine (6-OHDA)-induced SH-SY5Y cells. Iso activated AKT/mTOR signaling pathway via inhibiting Fos-like antigen (FOSL1) in 6-OHDA-induced SH-SY5Y cells. Overexpression of FOSL1 attenuated the protective effect of Iso against 6-OHDA-induced neuronal damage in SH-SY5Y cells. [ABSTRACT FROM AUTHOR]