Recent progress in biomimetic nanomedicines based on versatile targeting strategy for atherosclerosis therapy.

Atherosclerosis (AS) is considered to be one of the major causes of cardiovascular disease. Its pathological microenvironment is characterised by increased production of reactive oxygen species, lipid oxides, and excessive inflammatory factors, which accumulate at the monolayer endothelial cells in the vascular wall to form AS plaques. Therefore, intervention in the pathological microenvironment would be beneficial in delaying AS. Researchers have designed biomimetic nanomedicines with excellent biocompatibility and the ability to avoid being cleared by the immune system through different therapeutic strategies to achieve better therapeutic effects for the characteristics of AS. Biomimetic nanomedicines can further enhance delivery efficiency and improve treatment efficacy due to their good biocompatibility and ability to evade clearance by the immune system. Biomimetic nanomedicines based on therapeutic strategies such as neutralising inflammatory factors, ROS scavengers, lipid clearance and integration of diagnosis and treatment are versatile approaches for effective treatment of AS. The review firstly summarises the targeting therapeutic strategy of biomimetic nanomedicine for AS in recent 5 years. Biomimetic nanomedicines using cell membranes, proteins, and extracellular vesicles as carriers have been developed for AS.

Efficacy and Safety of Transarterial Chemoembolization Plus Donafenib with or without Immune Checkpoint Inhibitors as the First-Line Treatment for Unresectable Hepatocellular Carcinoma: A Propensity Score Matching Analysis.

Purpose: To compare the efficacy and safety of transarterial chemoembolization (TACE) plus donafenib with immune checkpoint inhibitors (ICIs) (T+D+I) versus TACE plus donafenib (T+D) as the first-line treatment for patients with unresectable hepatocellular carcinoma (HCC). Methods: This retrospective study included patients with unresectable HCC who received T+D+I or T+D between June 2021 and February 2023. The tumor response was analyzed according to the modified Response Evaluation Criteria in Solid Tumors. The objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and treatment-related adverse events (TRAEs) in the two groups were compared before and after propensity score matching (PSM). Cox's proportional-hazards regression model was used to analyze factors affecting PFS and OS. Results: This study included 69 patients: 41 patients in the T+D group and 28 patients in the T+D+I group. After PSM, 26 patients in each group were analyzed. Patients in the T+D+I group had a higher DCR (96.2% vs 73.1%, P = 0.021), longer median PFS (13.1 vs 7.2 months, P = 0.017), and longer median OS (23.1 vs 14.7 months, P = 0.021) than those in the T+D group. The ORR in the two groups was similar (53.8% vs 50.0%, P = 0.781). Multivariate analyses revealed that T+D+I treatment and total bilirubin levels of <20 µmol/L were independent prognostic factors for long PFS. T+D+I treatment, Child-Pugh class A, and single-lobe tumor distribution were independent prognostic factors for long OS. The incidence of TRAEs in the two groups was similar (P > 0.05). Conclusion: In comparison with TACE plus donafenib, TACE plus donafenib with ICIs could significantly improve DCR, PFS, and OS as a potential first-line treatment for unresectable HCC with an acceptable safety profile.

Inducing the Abscopal Effect in Liver Cancer Treatment: The Impact of Microwave Ablation Power Levels and PD-1 Antibody Therapy.

Microwave ablation (MWA) is an effective treatment for liver cancer (LC), but its impact on distant tumors remains to be fully elucidated. This study investigated the abscopal effects triggered by MWA treatment of LC, at different power levels and with or without combined immune checkpoint inhibition (ICI). We established a mouse model with bilateral subcutaneous LC and applied MWA of varied power levels to ablate the right-sided tumor, with or without immunotherapy. Left-sided tumor growth was monitored to assess the abscopal effect. Immune cell infiltration and distant tumor neovascularization were quantified via immunohistochemistry, revealing insights into the tumor microenvironment and neovascularization status. Th1- and Th2-type cytokine concentrations in peripheral blood were measured using ELISA to evaluate systemic immunological changes. It was found that MWA alone, especially at lower power, promoted distant tumor growth. On the contrary, combining high-power MWA with anti-programmed death (PD)-1 therapy promoted CD8+ T-cell infiltration, reduced regulatory T-cell infiltration, upregulated a Th1-type cytokine (TNF-α) in peripheral blood, and inhibited distant tumor growth. In summary, combining high-power MWA with ICI significantly enhances systemic antitumor immune responses and activates the abscopal effect, offering a facile and robust strategy for improving treatment outcomes.

Ferritin Nanocaged Doxorubicin Potentiates Chemo-Immunotherapy against Hepatocellular Carcinoma via Immunogenic Cell Death.

Although immunotherapy of hepatocellular carcinoma using immune checkpoint inhibitors has achieved certain success, only a subset of patients benefits from this therapeutic strategy. The combination of immunostimulatory chemotherapeutics represents a promising strategy to enhance the effectiveness of immunotherapy. However, it is hampered by the poor delivery of conventional chemotherapeutics. Here, it is shown that H-ferritin nanocages loaded with doxorubicin (DOX@HFn) show potent chemo-immunotherapy in hepatocellular carcinoma tumor models. DOX@HFn is constructed with uniform size, high stability, favorable drug loading, and intracellular acidity-driven drug release. The receptor-mediated targeting of DOX@HFn to liver cancer cells promote cellular uptake and tumor penetration in vitro and in vivo. DOX@HFn triggers immunogenic cell death to tumor cells and promotes the subsequent activation and maturation of dendritic cells. In vivo studies in H22 subcutaneous hepatoma demonstrate that DOX@HFn significantly inhibits the tumor growth with >30% tumors completely eliminated, while alleviating the systemic toxicity of free DOX. DOX@HFn also exhibits robust antitumor immune response and tumoricidal effect in a more aggressive Hepa1-6 orthotopic liver tumor model, which is confirmed by the in situ magnetic resonance imaging and transcriptome sequencing. This study provides a facile and robust strategy to improve therapeutic efficacy of liver cancer.

Clinical Implications of Phenotypes of Hemodialysis Patients With Central Venous Occlusion or Central Venous Stenosis Defined by Cluster Analysis.

Objective: This study aims to investigate the association between clinical factors of patients with central (superior vena cava, brachiocephalic, or subclavian) venous occlusion or central venous stenosis (CVO/CVS) and the difficulty of interventional recanalization as well as the duration of postoperative patency. Methods: A total of 103 hemodialysis patients with CVO/CVS treated with endovascular treatment were enrolled. The two-step cluster analysis was selected to differentiate the cases into distinct phenotypes automatically. Differences in characteristics, the difficulty of interventional recanalization, and the duration of postoperative primary patency time between the two clusters were statistically compared. Results: The 103 cases were divided into distinct two clusters by the two-step cluster analysis with 48 (46.6%) in cluster 1 and 55 (53.4%) in cluster 2. Compared to cluster 2, patients in cluster 1 have a higher proportion of blunt stump, side branches, occlusion lesions >2 cm, calcification, or organization. Moreover, the above four factors were, in turn, the most critical four predictors distinguishing 103 patients into two clusters. The remaining six factors were, in turn, occlusion located in the superior vena cava (SVC), duration of central venous catheterization (CVC), lesion location, vessel diameter, number of CVC, and previously failed lesion. Of the four most important factors, with the exception of occlusion lesions exceeding 2 cm, there were significant differences in the length of procedure time between the groups grouped by the remaining three factors. And there was a significant difference in the primary patency rate between the group with blunt stump and the group without blunt stump and also between the group with occlusion lesions ≥ 2 cm and the group with occlusion lesions <2 cm. The operation time of cluster 1 was longer than that of cluster 2. In terms of postoperative patency time, the primary patency time was significantly longer in the patients of cluster 2 compared with cluster 1 (P = 0.025). Conclusion: Patients were divided into distinct two clusters. CVO/CVS of patients in cluster 1 was more challenging to be recanalized than that in cluster 2, and the primary patency time was significantly longer in the patients of cluster 2 compared with cluster 1. Blunt stump, side branches, occlusion lesions exceeding 2 cm, and calcification or organization are the four most critical predictors distinguishing 103 patients into two clusters.

The earlier, the better: The beneficial effect of different timepoints of the preoperative transarterial embolization on ameliorating operative blood loss and operative time for carotid body tumors.

BACKGROUND: To explore the effect of the optimal time interval from preoperative transarterial embolization to surgery of carotid body tumors by analyzing surgery-related indicators. METHODS: This single-center retrospective review included 103 patients and 108 carotid body tumor resections performed between June 2010 and June 2020. All carotid body tumors were divided into three groups based on interval time between transarterial embolization and surgery: 1-day group (G1), 2-day group (G2), and 3-day group (G3). Demographics, inflammatory biomarkers, periprocedural details, and postoperative outcomes were analyzed. RESULTS: Among 103 patients, 48.54% were women, and the mean age was 37.07 years. The tumor sizes were 43.83, 44.31, and 42.84 mm in G1, G2, and G3, respectively, and the blood loss and operative time were 163.68, 331.54, and 683.68 mL, and 182.32, 216.31, and 280.79 mins with the prolonged time interval, respectively. Compared with pretransarterial embolization, the expression of white blood cells (109/L) and neutrophils (109/L) were obviously increased post-transarterial embolization in the three groups (G1: white blood cells 6.81 vs 9.32; neutrophils 0.54 vs 0.74, all P < .05. G2: white blood cells 7.19 vs 10.01, P = .118; neutrophils 0.54 vs 0.77, P < .05. G3: white blood cells 7.08 v. 12.37; neutrophils 0.59 vs 0.80, all P < .05), and those in G3 were significantly higher than those in G1. The incidences of revascularization, which was 30.26%, 53.85%, and 42.10%, and adverse events (26.32%, 30.77%, and 21.05%) were not significantly different among G1, G2, and G3. CONCLUSION: The optimal time interval between preoperative transarterial embolization and surgical resection resulted as 1 day as patients in this group showed obvious lower blood loss and shorter duration of operation than patients in other groups. Both inflammation and recanalization provided support for these results at some extent.

Gastrodin protects against LPS-induced acute lung injury by activating Nrf2 signaling pathway.

Gastrodin (GAS), a phenolic glucoside derived from Gastrodiaelata Blume, has been reported to have anti-inflammatory effect. The aim of this study was to investigate the effects of GAS on LPS-induced acute lung injury in mice. ALI was induced by the intranasal administration of LPS and GAS was given 1 h or 12 h after LPS treatment. The results indicated that GAS treatment markedly attenuated the damage of lung injury induced by LPS. GAS attenuated the activity of myeloperoxidase (MPO) and down-regulated the levels of pro-inflammatory cytokines TNF-α, IL-6 and IL-1ß in BALF. LPS-induced lung edema and lung function were also reversed by GAS. Furthermore, GAS was found to inhibit LPS-induced inflammatory cells infiltration. In addition, treatment of GAS inhibited LPS-induced NF-κB activation and up-regulated the expression of Nrf2 and HO-1. In conclusion, our results indicated that GAS had anti-inflammatory effects on LPS-induced acute lung injury. The anti-inflammatory mechanism of GAS was through the inhibition of NF-κB and activation of Nrf2 signaling pathways.

RAGE deficiency attenuates the protective effect of Lidocaine against sepsis-induced acute lung injury.

Lidocaine (Lido) is reported to suppress inflammatory responses and exhibit a therapeutic effect in models of cecal ligation and puncture (CLP)-induced acute lung injury (ALI). The receptor for advanced glycation end product (RAGE) exerts pro-inflammatory effects by enhancing pro-inflammatory cytokine production. However, the precise mechanism by which Lido confers protection against ALI is not clear. ALI was induced in RAGE WT and RAGE knockout (KO) rats using cecal ligation and puncture (CLP) operations for 24 h. The results showed that Lido significantly inhibited CLP-induced lung inflammation and histopathological lung injury. Furthermore, Lido significantly reduced CLP-induced upregulation of HMGB1 and RAGE expression and activation of the NF-κB and MAPK signaling pathways. With the use of RAGE KO rats, we demonstrate here that RAGE deficiency attenuates the protective effect of Lido against CLP-induced lung inflammatory cell infiltration and histopathological lung injury. These results suggest that RAGE deficiency attenuates the protective effect of Lido against CLP-induced ALI by attenuating the pro-inflammatory cytokines production.

The experiment research of neuroprotection of hypoperfusion postconditioning on cerebral ischemia.

In this study, we tested the hypothesis that the alternating of hypoperfusion and full reperfusion (hypoperfusion postconditioning) could improve neuroprotection on cerebral ischemia in rats and explored the role of TAp63 and △Np63 in this process. Eighty male Sprague Dawley rats were randomly divided into 4 groups: the sham group, the cerebral ischemic/reperfusion group (I/R), the hypoperfusion group 1 (HR1), and the hypoperfusion group 2 (HR2). Cerebral ischemia was established by clamping the bilateral common carotid artery with hypotension for 20 minutes. For the rats in the HR1 group, the blood pressure was maintained to 80 to 90 mm Hg in clamping bilateral common carotid artery minutes and then unclamped. For the rats in the HR2 group, the clamping was performed at one side of the common carotid artery and one half of the other side of common carotid artery. Neurologic behavior scores in the I/R, HR1, and HR2 groups decreased significantly after cerebral ischemia, and scores in the HR2 group were significantly higher than those in the I/R group (P < 0.05). Neuronal densities in the HR1 and HR2 groups were significantly higher than that in the I/R group (P < 0.05). Neuronal apoptosis in the HR1 and HR2 groups was significantly lower than that in the I/R group (P < 0.05). TAp63 and S100ß concentration decreased, and △Np63 increased significantly in the HR1 and HR2 groups as compared with the I/R group (P < 0.05). No significant difference in these parameters between the HR1 and HR2 groups (P > 0.05). Alternating of hypoperfusion and normal perfusion postconditioning had neuroprotection function on cerebral ischemia in the rats. This could relate with decreasing expression of TAp63 and increasing expression of △Np63 in hippocampal region of the first area in the hippocampal circuit to inhibit neuronal apoptosis.