Polyphenol-Based Self-Assembled Nanomedicine for a Three-Pronged Approach to Reversing Tumor Immunosuppression.

The challenges of multi-pathway immune resistance and systemic toxicity caused by the direct injection of immune checkpoint inhibitors are critical factors that compromise the effectiveness of clinical immune checkpoint blockade therapy. In this context, natural polyphenols have been employed as the primary component to construct a targeted and acid-responsive PD-L1 antibody (αPD-L1) delivery nanoplatform. This platform incorporates garcinol, an inhibitor of the Nuclear Factor Kappa-B (NF-κB) signaling pathway, to regulate pro-tumor immune escape cytokines and regulatory T cells. Additionally, the nanoplatform has been verified to induce immunogenic cell death (ICD), which promotes the maturation of dendritic cells and enhances the activity of cytotoxic T lymphocytes. In vivo and in vitro experimental results demonstrated that the nanoplatform can boost the immune response through a PD-L1 and NF-κB blocking/ICD inducing three-pronged strategy, thereby effectively combating tumor growth and metastasis.

An "AND" logic gate-based supramolecular therapeutic nanoplatform for combatting drug-resistant non-small cell lung cancer.

Despite targeted therapies like epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), non-small cell lung cancer (NSCLC) remains a clinical challenge due to drug resistance hampering their efficacy. Here, we designed an "AND" logic gate-based supramolecular therapeutic platform (HA-BPY-GEF-NPs) for the treatment of EGFR-TKI resistant NSCLC. This system integrates both internal and external stimuli-responsive mechanisms that need to be activated in a preset sequence, enabling it to precisely control drug release behavior for enhancing therapeutic precision. By programming the system to respond to sequential near-infrared (NIR) irradiation and enzyme (cathepsin B) inputs, the release of gefitinib is effectively confined to the tumor region. Moreover, the NIR irradiation induces reactive oxygen species production, suppressing tumor growth and inhibiting bypass signaling pathways. The designed drug delivery system offers a highly controlled and targeted therapeutic approach, effectively inhibiting tumor growth, suppressing bypass signaling pathways, and overcoming EGFR-TKI resistance, thus offering a potential solution for maximizing therapeutic benefits.

High-mobility group box 1 and its related receptors: potential therapeutic targets for contrast-induced acute kidney injury.

Percutaneous coronary intervention (PCI) is a crucial diagnostic and therapeutic approach for coronary heart disease. Contrast agents' exposure during PCI is associated with a risk of contrast-induced acute kidney injury (CI-AKI). CI-AKI is characterized by a sudden decline in renal function occurring as a result of exposure to intravascular contrast agents, which is associated with an increased risk of poor prognosis. The pathophysiological mechanisms underlying CI-AKI involve renal medullary hypoxia, direct cytotoxic effects, endoplasmic reticulum stress, inflammation, oxidative stress, and apoptosis. To date, there is no effective therapy for CI-AKI. High-mobility group box 1 (HMGB1), as a damage-associated molecular pattern molecule, is released extracellularly by damaged cells or activated immune cells and binds to related receptors, including toll-like receptors and receptor for advanced glycation end product. In renal injury, HMGB1 is expressed in renal tubular epithelial cells, macrophages, endothelial cells, and glomerular cells, involved in the pathogenesis of various kidney diseases by activating its receptors. Therefore, this review provides a theoretical basis for HMGB1 as a therapeutic intervention target for CI-AKI.

NIR-dye bridged human serum albumin reassemblies for effective photothermal therapy of tumor.

Human serum albumin (HSA) based drug delivery platforms that feature desirable biocompatibility and pharmacokinetic property are rapidly developed for tumor-targeted drug delivery. Even though various HSA-based platforms have been established, it is still of great significance to develop more efficient preparation technology to broaden the therapeutic applications of HSA-based nano-carriers. Here we report a bridging strategy that unfastens HSA to polypeptide chains and subsequently crosslinks these chains by a bridge-like molecule (BPY-Mal2) to afford the HSA reassemblies formulation (BPY@HSA) with enhanced loading capacity, endowing the BPY@HSA with uniformed size, high photothermal efficacy, and favorable therapeutic features. Both in vitro and in vivo studies demonstrate that the BPY@HSA presents higher delivery efficacy and more prominent photothermal therapeutic performance than that of the conventionally prepared formulation. The feasibility in preparation, stability, high photothermal conversion efficacy, and biocompatibility of BPY@HSA may facilitate it as an efficient photothermal agents (PTAs) for tumor photothermal therapy (PTT). This work provides a facile strategy to enhance the loading capacity of HSA-based crosslinking platforms in order to improve delivery efficacy and therapeutic effect.

Dextran-based micelles for combinational chemo-photodynamic therapy of tumors via in vivo chemiluminescence.

Natural polysaccharides, represented by dextran, chitosan, and hyaluronic acid, are widely approved for use as pharmaceutical excipients and are important carrier materials for the design of advanced drug delivery systems, particularly in the field of anticancer drug delivery. The combination of stimuli-activable prodrug based chemotherapy and photodynamic therapy (PDT) has attracted increasing attention. Recent studies have verified the effectiveness of this strategy in the treatment of multiple aggressive cancers. However, in such combination, the stimuli-responsive chemotherapy and PDT have their own problems that need to be overcome. The uneven distribution of endogenous stimuli within tumor tissues makes it difficult for prodrug to be completely activated. And the inadequate tissue penetration depth of external light results in low efficiency of PDT. Aiming at these two bottlenecks, we designed a biocompatible dextran based - multi-component nanomedicine (PCL-NPs) that integrate a chemiluminescence agent luminol, a photosensitizer chlorine e6 (Ce6), and a reactive oxygen species (ROS)-activable thioketal-based paclitaxel (PTX) prodrug. The presence of overexpressed hydrogen peroxide (H2O2) inside tumor oxidizes the luminol moiety to generate in-situ light for PDT through chemiluminescence resonance energy transfer (CRET). The singlet oxygen (1O2) produced in this process not only directly kills tumor cells but also amplifies oxidative stress to accelerate the activation of PTX prodrug. We propose that the PCL-NPs have great therapeutic potential by simultaneously enhancing chemotherapy and PDT in a combination therapy.

Mussel-inspired "plug-and-play" hydrogel glue for postoperative tumor recurrence and wound infection inhibition.

Currently, clinical tumor resection is faced with two options: open and minimally invasive surgery. Open surgery is easy to completely remove the lesion but is prone to infection, while minimally invasive surgery recovers faster but may cause tumor recurrence. To fill the shortcomings of the two surgical modes and make the choice for tumor resection more effortlessly, we developed a postoperative black phosphorus-Ag nanocomposites-loaded dopamine-modified hyaluronic acid-Pluronic® F127 (BP-Ag@HA-DA-Plu) hydrogel implantation system that can prevent tumor recurrence and wound infection simultaneously. Experiments have shown that the hydrogel system combined with 808 nm near-infrared (NIR) irradiation has excellent anti-tumor, antibacterial, and wound healing abilities. Additionally, unlike existing surgical hydrogel products that require inconvenient in-situ cross-linking, the BP-Ag@HA-DA-Plu hydrogel system offers "plug-and-play" functionality during surgery due to its thermo-responsiveness, injectability, and adhesion, thereby greatly improving the efficiency of surgery.

Vaspin Alleviates Sepsis-Induced Cardiac Injury and Cardiac Inflammation by Inhibiting Kallikrein 7 in Mice.

Background: Vaspin is an important adipokine that is involved in cardiovascular diseases. This study is aimed at investigating whether vaspin participates in sepsis-induced cardiac injury and explored the possible mechanism. Methods: First, cecal ligation and puncture (CLP) and lipopolysaccharide (LPS) were used to establish a mouse model of sepsis, and cardiac vaspin expression was examined. In addition, after pretreatment with vaspin or phosphate-buffered saline (PBS), wild-type (WT) mice underwent CLP to establish a septic model and received sham as a control. Finally, WT mice and kallikrein 7 (KLK7-/-) mice were underwent CLP with or without vaspin pretreatment. Results: Mice that underwent CLP and were administered LPS exhibited increased vaspin expression in both the heart and serum compared with sham- or saline-treated mice. In CLP mice, pretreatment with vaspin reduced mortality and alleviated the expression of cardiac injury markers and cardiac dysfunction. In addition, vaspin reduced the cardiac levels of CD45+ cells and CD68+ cells, alleviated the cardiac inflammatory response, and reduced cardiomyocyte apoptosis. The protective effects of vaspin on CLP mice were masked by the deletion of KLK7, which was demonstrated to be a downstream signal of vaspin. Conclusions: Vaspin alleviates cardiac inflammation and plays a protective role in sepsis-induced cardiac injury by reducing KLK7 expression.

High mobility group box 1 and homocysteine as preprocedural predictors for contrast-induced acute kidney injury after percutaneous coronary artery intervention.

PURPOSE: High mobility group box 1 (HMGB1) and homocysteine (Hcy) play important roles in contrast-induced acute kidney injury (CI-AKI). We compared HMGB1 to Hcy as preprocedural predictors for CI-AKI in coronary artery disease (CAD) patients after percutaneous coronary artery intervention (PCI). METHODS: We included 257 eligible patients who were categorized into CI-AKI ( +) and CI-AKI ( -) group. The differences in clinical characteristics and biochemical indexes between two groups were analyzed. RESULTS: We observed that thirty-eight (14.8%) of 257 eligible CAD patients developed CI-AKI. HMGB1 (14.65 [11.13-24.89] vs 10.88 [7.94-13.23], p < 0.001) and Hcy (14.07 [12.07-17.31] vs 12.09 [10.71-13.47], p < 0.001) increased significantly in CI-AKI ( +) group. Both age (r = 0.210, p = 0.001), serum creatinine (r = 0.509, p < 0.001), eGFR (r = - 0.459, p < 0.001) and Hcy (r = 0.531, p < 0.001) were significantly correlated with HMGB1. Among all patients, HMGB1 (OR 1.181, 95% CI 1.081-1.290, p < 0.001) and Hcy (OR 1.260, 95% CI 1.066-1.489, p = 0.007) were independent predictors for the development of CI-AKI. We built the propensity score matching (PSM) using 38 pairs of patients. After adjustment, HMGB1 (OR 1.169, 95% CI 1.035-1.322, p = 0.012) and Hcy (OR 1.457, 95% CI 1.064-1.997, p = 0.019) were also independent predictors for the development of CI-AKI. Both HMGB1 (AUC: 0.704, 95% CI: 0.588-0.819, p = 0.002) and Hcy (AUC: 0.708, 95% CI: 0.593-0.823, p = 0.002) had predictive values for CI-AKI. CONCLUSION: There is a significant positive association between HMGB1 and Hcy in CAD patients. Both HMGB1 and Hcy are potential preprocedural predictors of CI-AKI after PCI.

Association between serum angiopoietin-2 concentrations and periprocedural myocardial injury in patients undergoing elective percutaneous coronary intervention.

Angiopoietin-2 (Ang-2) is a proangiogenic factor that mediates inflammation and atherosclerosis. We evaluated the predictive value of circulating Ang-2 levels for periprocedural myocardial injury (PMI) in 145 patients undergoing elective percutaneous coronary intervention (PCI), and investigated whether post-PCI Ang-2 levels are influenced by PMI. PMI was defined as a post-procedural troponin elevation above the 5×99th percentile upper reference limit. Blood samples for Ang-2 analysis were collected at admission and on postoperative days 1 and 3. PMI occurred in 40 patients (28%). At baseline, there was no difference in Ang-2 levels between PMI and non-PMI patients (P=0.554). However, a significant interaction effect between PMI occurrence and time on Ang-2 levels was observed (interaction P=0.036). Although serum Ang-2 levels in non-PMI patients gradually decreased, Ang-2 levels in PMI patients did not change between different time-points. Multiple logistic regression analysis revealed that age, total stent length, and serum levels of N-terminal pro-brain natriuretic peptide were independent PMI predictors. These findings indicate that pre-procedural Ang-2 levels do not impact PMI occurrence after elective PCI. However, changes in Ang-2 levels after the procedure are closely related to PMI.

Cyanine-based NIR fluorescent probe for monitoring H2S and imaging in living cells and in vivo.

As a critical gaseous signaling molecule, H2S is involved in various biological processes. To deeper study the physiological and pathological roles of H2S, convenient and efficient detection techniques for endogenous H2S in vivo are still in urgent demand. Herein, we reported a new turn-on Near-infrared (NIR) fluorescence probe NIR-H2S based on thiolysis reactions for detection of H2S. The probe possessed many excellent properties including high sensitivity and selectivity, good cell-membrane permeability, and low cytotoxicity. In vitro, NIR-H2S showed a 58-fold fluorescence enhancement when reacted with H2S in a buffer and displayed a good linear relationship (r = 0.9925) in a rather wide concentration range of H2S (0-500 µM). Furthermore, NIR-H2S was successfully employed in monitoring endogenous H2S induced by D-Cys in living cancer cells and mice. These results indicated that NIR-H2S had great potentiality in detecting cellular H2S in living animals and being applied to cancer diagnosis.

[Application of laparoscopy in ectopic pregnancy complicated with intrauterine pregnancy: reports of 5 cases].

OBJECTIVE: To investigate the effects of laparoscopy in treating ectopic pregnancy complicated with intrauterine pregnancy. METHOD: Laparoscopy was performed in 5 patients with ectopic pregnancy complicated with intrauterine pregnancy. RESULTS: The ectopic pregnancy tissue or the damaged fallopian tube was successfully excised laparoscopically. CONCLUSION: Laparoscopy is safe for treating ectopic pregnancy complicated with intrauterine pregnancy, causing minimal injuries and less disturbance to intrauterine pregnancy and ensuring rapid recovery.

[Comparative study of the impacts of laparoscopic and open laparotomic surgeries on oxidative stress in patients with uterine myomas].

OBJECTIVE: To evaluate the impact of laparoscopic surgery on oxidative stress in patients with uterine myomas. METHODS: Plasma malondialdehyde (MDA), antioxidant activity (AOA), and glutathione peroxidase (GPx) activity in 20 patients with uterine myomas were measured before, at the end of (5 min after deflation), and 24 h after laparoscopic surgery, for comparison with the measurements in 20 patients receiving laparotomic surgery at the same time points. RESULTS: Immediately following laparoscopic surgery, plasma MDA level increased significantly as compared with the preoperative level (P<0.01) and recovered the normal level 24 h after the operation; but in laparotomic surgery, plasma MDA level underwent a slight increase in the immediately early postoperative stage and continued to increase 24 h after the operation. In laparoscopic surgery, GPx and AOA decreased significantly in the early postoperative stage (P<0.01) and recovered to some extent 24 h postoperatively, whereas in laparotomic surgery, GPx and AOA slightly decreased immediately following the operation and further decreased 24 h after the operation. Compared with patients receiving laparotomic surgery, laparoscopic patients had significantly lower plasma MDA level (P<0.01) and significantly higher GPx activity (P<0.01) with comparable AOA level (P=0.33) 24 h after the operation. CONCLUSION: Free radical produces at the end of a laparoscopic procedure, possibly as a result of ischemia-reperfusion induced by the inflation and deflation of the pneumoperitoneum.