Combination of betulinic acid and EGFR-TKIs exerts synergistic anti-tumor effects against wild-type EGFR NSCLC by inducing autophagy-related cell death via EGFR signaling pathway.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung cancer patients with mutated EGFR. However, the efficacy of EGFR-TKIs in wild-type EGFR tumors has been shown to be marginal. Methods that can sensitize EGFR-TKIs to EGFR wild-type NSCLC remain rare. Hence, we determined whether combination treatment can maximize the therapeutic efficacy of EGFR-TKIs. METHODS: We established a focused drug screening system to investigate candidates for overcoming the intrinsic resistance of wild-type EGFR NSCLC to EGFR-TKIs. Molecular docking assays and western blotting were used to identify the binding mode and blocking effect of the candidate compounds. Proliferation assays, analyses of drug interactions, colony formation assays, flow cytometry and nude mice xenograft models were used to determine the effects and investigate the molecular mechanism of the combination treatment. RESULTS: Betulinic acid (BA) is effective at targeting EGFR and synergizes with EGFR-TKIs (gefitinib and osimertinib) preferentially against wild-type EGFR. BA showed inhibitory activity due to its interaction with the ATP-binding pocket of EGFR and dramatically enhanced the suppressive effects of EGFR-TKIs by blocking EGFR and modulating the EGFR-ATK-mTOR axis. Mechanistic studies revealed that the combination strategy activated EGFR-induced autophagic cell death and that the EGFR-AKT-mTOR signaling pathway was essential for completing autophagy and cell cycle arrest. Activation of the mTOR pathway or blockade of autophagy by specific chemical agents markedly attenuated the effect of cell cycle arrest. In vivo administration of the combination treatment caused marked tumor regression in the A549 xenografts. CONCLUSIONS: BA is a potential wild-type EGFR inhibitor that plays a critical role in sensitizing EGFR-TKI activity. BA combined with an EGFR-TKI effectively suppressed the proliferation and survival of intrinsically resistant lung cancer cells via the inhibition of EGFR as well as the induction of autophagy-related cell death, indicating that BA combined with an EGFR-TKI may be a potential therapeutic strategy for overcoming the primary resistance of wild-type EGFR-positive lung cancers.

The Association Between S100A12 Protein and C-Reactive Protein with Malignant Ventricular Arrhythmias Following Acute Myocardial Infarction in the Elderly.

Objective: To investigate the association of S100A12 protein and C-reactive protein (CRP) with the onset of malignant ventricular arrhythmias (MVA) after acute myocardial infarction (AMI) in the elderly. Methods: A total of 159 elderly AMI patients admitted to Chongming Hospital affiliated to Shanghai University of Medicine & Health Sciences from January 2018 to January 2023 were enrolled in the study. CRP levels were determined using an automatic biochemical analyzer, and S100A12 levels were measured using enzyme-linked immunosorbent assay (ELISA). Patients were categorized based on the Lown classification into groups without MVA and with MVA. Univariate analysis was initially performed to identify independent variables, followed by multivariate logistic regression to determine the risk factors for malignant ventricular arrhythmias post-AMI. The predictive value of S100A12 protein and CRP for malignant ventricular arrhythmias after acute myocardial infarction in the elderly was analyzed using the receiver operating characteristic (ROC) curve. Results: Among the 159 patients with AMI, 27 (17%) had MVA. Multivariate logistic regression analysis indicated that both S100A12 protein and CRP could be independent risk factors for malignant ventricular arrhythmias following acute myocardial infarction in the elderly (p < 0.05). The area under the ROC curve showed the area under the curve (AUC) for S100A12 protein to be 0.7147, for CRP 0.7356, and for the combined diagnosis 0.8350 (p < 0.05). Conclusion: S100A12 protein and CRP are independent risk factors for MVA after MI in the elderly. The combined application of S100A12 protein and CRP has higher diagnostic sensitivity and specificity.

Sirtuin 5 Alleviates Liver Ischemia/Reperfusion Injury by Regulating Mitochondrial Succinylation and Oxidative Stress.

Aims: Mitochondrial dysfunction is the primary mechanism of liver ischemia/reperfusion (I/R) injury. The lysine desuccinylase sirtuin 5 (SIRT5) is a global regulator of the mitochondrial succinylome and has pivotal roles in mitochondrial metabolism and function; however, its hepatoprotective capacity in liver I/R remains unclear. In this study, we established liver I/R model in SIRT5-silenced and SIRT5-overexpressed mice to examine the role and precise mechanisms of SIRT5 in liver I/R injury. Results: Succinylation was strongly enriched in liver mitochondria during I/R, and inhibiting mitochondrial succinylation significantly attenuated liver I/R injury. Importantly, the levels of the desuccinylase SIRT5 were notably decreased in liver transplant patients, as well as in mice subjected to I/R and in AML12 cells exposed to hypoxia/reoxygenation. Furthermore, SIRT5 significantly ameliorated liver I/R-induced oxidative injury, apoptosis, and inflammation by regulating mitochondrial oxidative stress and function. Intriguingly, the hepatoprotective effect of SIRT5 was mediated by PRDX3. Mechanistically, SIRT5 specifically desuccinylated PRDX3 at the K84 site, which enabled PRDX3 to alleviate mitochondrial oxidative stress during liver I/R. Innovation: This study denoted the new effect and mechanism of SIRT5 in regulating mitochondrial oxidative stress through lysine desuccinylation, thus preventing liver I/R injury. Conclusions: Our findings demonstrate for the first time that SIRT5 is a key mediator of liver I/R that regulates mitochondrial oxidative stress through the desuccinylation of PRDX3, which provides a novel strategy to prevent liver I/R injury. Antioxid. Redox Signal. 40, 616-631.

Advances in Polymeric Micelles: Responsive and Targeting Approaches for Cancer Immunotherapy in the Tumor Microenvironment.

In recent years, to treat a diverse array of cancer forms, considerable advancements have been achieved in the field of cancer immunotherapies. However, these therapies encounter multiple challenges in clinical practice, such as high immune-mediated toxicity, insufficient accumulation in cancer tissues, and undesired off-target reactions. To tackle these limitations and enhance bioavailability, polymer micelles present potential solutions by enabling precise drug delivery to the target site, thus amplifying the effectiveness of immunotherapy. This review article offers an extensive survey of recent progress in cancer immunotherapy strategies utilizing micelles. These strategies include responsive and remodeling approaches to the tumor microenvironment (TME), modulation of immunosuppressive cells within the TME, enhancement of immune checkpoint inhibitors, utilization of cancer vaccine platforms, modulation of antigen presentation, manipulation of engineered T cells, and targeting other components of the TME. Subsequently, we delve into the present state and constraints linked to the clinical utilization of polymeric micelles. Collectively, polymer micelles demonstrate excellent prospects in tumor immunotherapy by effectively addressing the challenges associated with conventional cancer immunotherapies.

Inhibition of tumor metastasis by targeted daunorubicin and dioscin codelivery liposomes modified with PFV for the treatment of non-small-cell lung cancer.

Background: Chemotherapy for non-small-cell lung cancer (NSCLC) still leads to unsatisfactory clinical prognosis because of poor active targeting and tumor metastasis. Purpose: The objective of this study was to construct a kind of PFV peptide modified targeted daunorubicin and dioscin codelivery liposomes, which could enhance tumor targeting and inhibit tumor cell metastasis. Methods and results: Targeted daunorubicin and dioscin codelivery liposomes were prepared by film dispersion and the ammonium sulfate gradient method. With the ideal physicochemical properties, targeted daunorubicin and dioscin codelivery liposomes exhibited enhanced cellular uptake and showed strong cytotoxicity to tumor cells. The encapsulation of dioscin increased the inhibitory effects of daunorubicin on A549 cells, vasculogenic mimicry (VM) channels and tumor metastasis. The enhanced antimetastatic mechanism of the targeted liposomes was attributed to the downregulation of matrix metalloproteinase-2 (MMP-2), vascular endothelial cadherin (VE-Cad), transforming growth factor-ß1 (TGF-ß1) and hypoxia inducible factor-1α (HIF-1α). Meanwhile, the targeted daunorubicin and dioscin codelivery liposomes exhibited significant antitumor effects in tumor-bearing mice. H&E staining, immunohistochemistry with Ki-67 and TUNEL assay also showed the promoted antitumor activity of the targeted liposomes. Conclusion: Targeted daunorubicin and dioscin codelivery liposomes may provide an effective strategy for the treatment of NSCLC.

Proinflammatory cytokine IFN-γ, lncRNA BANCR and the occurrence of coronary artery disease.

AIMS: Coronary artery disease (CAD) ranks the leading cause of death globally. Interferon-γ (IFN-γ) gene, along with long noncoding RNA (lncRNA) BRAF-activated noncoding RNA (BANCR), could coordinately function in the occurrence of CAD. We hypothesized that level of IFN-γ, genetic variants of IFN-γ and BANCR gene should be associated with the occurrence of CAD. MATERIALS AND METHODS: A case-control study was conducted in Chinese population. KEY FINDINGS: We found that serum level of IFN-γ in CAD cases was significantly higher than that in controls (P < 0.001). Compared with the first quartile, all of the second (OR: 1.87; 95% CIs: 1.33-2.62), the third (OR: 1.79; 95% CIs: 1.30-2.45), and the fourth (OR: 3.98; 95% CIs: 2.59-6.12) quartiles of serum level of IFN-γ were associated with increased risk of CAD (P < 0.05). We found IFN-γ gene (rs2069705 and rs2430561), and 2 variants in lncRNA BANCR (rs6559446 and rs79823312) could increase CAD susceptibility in allelic and dominant model, while IFN-γ rs2069705 and rs2430561, BANCR rs79823312 were also associated with CAD risk in additive model. IFN-γ rs2069705 and rs2430561 were associated with higher level of serum IFN-γ in CAD patients (P < 0.001). SIGNIFICANCE: This study confirmed the crucial role of IFN-γ and lncRNA BANCR in the occurrence of CAD, and might serve as the biomarkers of CAD screening and prevention.