Supplementary Material for: Association between BMI and efficacy of SGLT2 inhibitors in patients with heart failure or at risk of heart failure: a meta-analysis based on randomized controlled trials

Introduction: This meta-analysis aimed to investigate the effect of SGLT2 inhibitors on the prognosis in patients with heart failure (HF) or at risk of heart failure across different body mass index (BMI). Methods: We searched PubMed, Embase, Web of Science, and Cochrane Library for all randomized controlled trials (RCTs) comparing SGLT2 inhibitors with placebo in patients with HF or at risk of HF and extracted relevant data up to April 2023 for meta-analysis. Results: A total of 29,500 patients were enrolled in the selected five studies. The results showed that patients treated with SGLT2 inhibitors had lower heart failure hospitalization (HHF) or cardiovascular (CV) mortality compared to those taking placebo (hazard ratio (HR)=0.73, p<0.001). Patients taking SGLT2 inhibitors also had a lower all-cause mortality rate than those taking placebo (HR=0.85, p=0.017). In BMI subgroup analysis, the HHF rate in the experimental group was lower than that in the control group at BMI ≤24.9 kg/m2, 25.0-29.9 kg/m2, and ≥30.0 kg/m2. There was no significant difference in CV mortality between the two groups at BMI ≤24.9 kg/m2 (HR=0.91, p=0.331) and 25.0-29.9 kg/m2 (HR=0.92, p=0.307). However, when the BMI was ≥30.0 kg/m2, CV mortality with SGLT2 inhibitors was lower than in the control group (HR=0.79, p=0.002). When patients had a BMI ≤24.9 kg/m2 (HR=0.85, p=0.033) and 25.0-29.9 kg/m2 (HR=0.83, p=0.046), the all-cause mortality was lower in the experimental group than in the control group. However, there was no significant difference between the two groups in patients with a BMI ≥30.0 kg/m2 (HR=0.87, p=0.094). Conclusion: SGLT2 inhibitors improve prognosis in patients with HF or at risk of HF. This effect is affected by BMI

Supplementary Material for: Palmitic Acid Curcumin Ester Facilitates Protection of Neuroblastoma against Oligomeric Aβ₄₀ Insult

<b><i>Background/Aims:</i></b> The generation of reactive oxygen species (ROS) caused by amyloid-β (Aβ) is considered to be one of mechanisms underlying the development of Alzheimer’s disease. Curcumin can attenuate Aβ-induced neurotoxicity through ROS scavenging, but the protective effect of intracellular curcumin on neurocyte membranes against extracellular Aβ may be compromised. To address this issue, we synthesized a palmitic acid curcumin ester (P-curcumin) which can be cultivated on the cell membrane and investigated the neuroprotective effect of P-curcumin and its interaction with Aβ. <b><i>Methods:</i></b> P-curcumin was prepared through chemical synthesis. Its structure was determined via nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). An MTT assay was used to assess Aβ cytotoxicity and the protective effect of P-curcumin on SH-SY5Y cells. The effect of P-curcumin on Aβ-induced ROS production <i>in vitro</i> and <i>in vivo</i> were assessed based on changes in dichlorofluorescein (DCF) fluorescence. A spectrophotometric method was employed to detect lipid peroxidation. To mimic the interaction of P-curcumin on cell membranes with Aβ, liposomes were prepared by thin film method. Finally, the interactions between free P-curcumin and P-curcumin cultivated on liposomes and Aβ were determined via spectrophotometry. <b><i>Results:</i></b> A novel derivative, palmitic acid curcumin ester was prepared and characterized. This curcumin, cultivated on the membranes of neurocytes, may prevent Aβ-mediated ROS production and may inhibit the direct interaction between Aβ and the cellular membrane. Furthermore, P-curcumin could scavenge Aβ-mediated ROS as curcumin <i>in vitro</i> and <i>in vivo</i>, and had the potential to prevent lipid peroxidation. Morphological analyses showed that P-curcumin was better than curcumin at protecting cell shape. To examine P-curcumin’s ability to attenuate direct interaction between Aβ and cell membranes, the binding affinity of Aβ to curcumin and P-curcumin was determined. The association constants for free P-curcumin and curcumin were 7.66 × 10⁴ M^-1 and 7.61 × 10⁵ M^-1, respectively. In the liposome-trapped state, the association constants were 3.71 × 10⁵ M^-1 for P-curcumin and 1.44× 10⁶ M^-1 for curcumin. With this data, the thermodynamic constants of P-curcumin association with soluble Aβ <i>(ΔH, ΔS</i>, and Δ<i>G</i>) were also determined. <b><i>Conclusion:</i></b> Cultivated curcumin weakened the direct interaction between Aβ and cell membranes and showed greater neuroprotective effects against Aβ insult than free curcumin

Supplementary Material for: Association Between Hypoxia-Inducible Factor-2α (HIF-2α) Expression and Colorectal Cancer and Its Prognostic Role: a Systematic Analysis

<b><i>Background/Aims:</i></b> Although some studies showed that HIF-2α expression was correlated with an unfavorable prognosis in colorectal cancer (CRC), the prognostic results remain conflicting in CRC. The present study was performed to evaluate the association between HIF-2α expression and the clinicopathological features of this disease and to examine the potential prognostic role of HIF-2α expression in CRC. <b><i>Methods:</i></b> Pooled odds ratios (ORs) or hazard ratios (HRs) were calculated from available publications, The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) datasets. Trial sequential analysis (TSA) was used to estimate the required sample information. <b><i>Results:</i></b> HIF-2α protein expression was more frequent in CRC than in normal colonic tissues (OR = 150.49, <i>P</i> < 0.001), higher in male than female CRC patients (OR = 1.47, <i>P</i> = 0.008), and lower in high-grade than low-grade CRC (OR = 0.49, <i>P</i> = 0.029). TSA verified the reliability of the above results. HIF-2α expression was not linked to the prognosis of CRC in overall survival (OS), disease-specific survival (DSS), metastasis-free survival, and relapse-free survival, and no significant correlation was found between HIF-2α alteration and OS or disease-free survival (DFS) of CRC. Expression of both HIF-2α and vascular endothelial growth factor (VEGFA, VEGFB, or VEGFC) was associated with a poor metastasis-free survival of CRC (HR = 6.95, HR = 113.51, and HR = 8.11, respectively). No association was observed between HIF-2α expression and DFS in other cancers, but HIF-2α expression was correlated with a worse DFS of CRC (HR = 1.23, <i>P</i> = 0.037). Moreover, HIF-2α expression was linked to a good survival benefit in some cancers (B-cell lymphoma and lung adenocarcinoma: OS, multiple myeloma: DSS, breast cancer: distant metastasis-free survival, liposarcoma: distant recurrence-free survival) (all HRs < 1, <i>Ps</i> < 0.05). <b><i>Conclusions:</i></b> HIF-2α expression may be associated with the carcinogenesis of CRC, which is higher in males than in females, negatively linked to tumor differentiation, and correlated with a worse DFS of CRC. Additional prospective studies are needed