Gene signatures of endoplasmic reticulum stress and mitophagy for prognostic risk prediction in lung adenocarcinoma.

Genes associated with endoplasmic reticulum stress (ERS) and mitophagy can be conducive to predicting solid tumour prognosis. The authors aimed to develop a prognosis prediction model for these genes in lung adenocarcinoma (LUAD). Relevant gene expression and clinical information were collected from public databases including Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA). A total of 265 differentially expressed genes was finally selected (71 up-regulated and 194 downregulated) in the LUAD dataset. Among these, 15 candidate ERS and mitophagy genes (ATG12, CSNK2A1, MAP1LC3A, MAP1LC3B, MFN2, PGAM5, PINK1, RPS27A, SQSTM1, SRC, UBA52, UBB, UBC, ULK1, and VDAC1) might be critical to LUAD based on the expression analysis after crossing with the ERS and mitochondrial autophagy genes. The prediction model demonstrated the ability to effectively predict the 5-, 3-, and 1-year prognoses of LUAD patients in both GEO and TCGA databases. Moreover, high VDAC1 expression was associated with poor overall survival in LUAD (p < 0.001), suggesting it might be a critical gene for LUAD prognosis prediction. Overall, the prognosis model based on ERS and mitophagy genes in LUAD can be useful for evaluating the prognosis of patients with LUAD, and VDAC1 may serve as a promising biomarker for LUAD prognosis.

Prognostic value of inflammatory nutritional scores in locally advanced esophageal squamous cell carcinoma patients undergoing neoadjuvant chemoimmunotherapy: a multicenter study in China.

Objective: This study investigates the prognostic significance of inflammatory nutritional scores in patients with locally advanced esophageal squamous cell carcinoma (LA-ESCC) undergoing neoadjuvant chemoimmunotherapy. Methods: A total of 190 LA-ESCC patients were recruited from three medical centers across China. Pre-treatment laboratory tests were utilized to calculate inflammatory nutritional scores. LASSO regression and multivariate logistic regression analyses were conducted to pinpoint predictors of pathological response. Kaplan-Meier and Cox regression analyses were employed to assess disease-free survival (DFS) prognostic factors. Results: The cohort comprised 154 males (81.05%) and 36 females (18.95%), with a median age of 61.4 years. Pathological complete response (pCR) was achieved in 17.38% of patients, while 44.78% attained major pathological response (MPR). LASSO and multivariate logistic regression analyses identified that hemoglobin, albumin, lymphocyte, and platelet (HALP) (P=0.02) as an independent predictors of MPR in LA-ESCC patients receiving neoadjuvant chemoimmunotherapy. Kaplan-Meier and log-rank tests indicated that patients with low HALP, MPR, ypT1-2, ypN0 and, ypTNM I stages had prolonged DFS (P < 0.05). Furthermore, univariate and multivariate Cox regression analyses underscored HALP (P = 0.019) and ypT (P = 0.029) as independent predictive factors for DFS in ESCC. Conclusion: Our study suggests that LA-ESCC patients with lower pre-treatment HALP scores exhibit improved pathological response and reduced recurrence rate. As a comprehensive index of inflammatory nutritional status, pre-treatment HALP may be a reliable prognostic marker in ESCC patients undergoing neoadjuvant chemoimmunotherapy.

Association between per- and polyfluoroalkyl substances exposure and prevalence of chronic obstructive pulmonary disease: The mediating role of serum albumin.

BACKGROUND: No study has examined the association between per- and polyfluoroalkyl substances (PFAS) exposure and chronic obstructive pulmonary disease (COPD) risk. This study aims to explore this relationship. METHODS: This study enrolled 4541 individuals who had available data on PFAS, COPD, and covariates from NHANES 2007-2018. Serum PFAS including perfluorohexane sulfonate (PFHxS), perfluorononanoic acid (PFNA), perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS) were analyzed, because of high detective rates. Considering the skew distribution of PFAS levels, the natural logarithm-transformed PFAS (Ln-PFAS) was used. Logistic regression analysis, restricted cubic spline (RCS), and weighted quantile sum (WQS) regression were performed to explore the single, nonlinear, and mixed effects. A mediating analysis was used to evaluate the mediated effects of albumin. RESULTS: Individuals with COPD had higher levels of PFHxS, PFNA, PFOA, and PFOS compared to those without COPD. Ln-PFNA (OR males: 1.92, 95 % CI:1.31 to 2.80, P: <0.001; OR females: 1.07, 95 % CI: 0.81 to 1.40, P: 0.636) and ln-PFOA (OR males: 2.17, 95 % CI:1.38 to 3.41, P: <0.001; OR females: 1.49, 95 % CI: 1.08 to 2.05, P: 0.016) were associated with COPD risk especially in males. The interaction between PFNA exposure and sex on COPD risk was significant (P interaction: <0.001). The RCS curve demonstrated the nonlinear relationship between the ln-PFOA (P nonlinear:0.001), ln-PFNA (P nonlinear:0.045), and COPD risk in males. WQS analysis showed mixed PFAS exposure was correlated with COPD risk in males (OR: 1.44, 95 % CI:1.18 to 1.75, P: <0.001). Albumin mediated the relationship between PFOA and COPD (mediated proportion: -17.94 %). CONCLUSION: This study concludes PFOA and PFNA are linked to a higher COPD risk in males, and serum albumin plays a mediating role in the relationship between PFOA and COPD. Thess findings are beneficial for the prevention of COPD. Further studies are required to explore potential mechanisms.

Amino acid-based metallo-supramolecular nanoassemblies capable of regulating cellular redox homeostasis for tumoricidal chemo-/photo-/catalytic combination therapy.

Nanozymes, as nanomaterials with natural enzyme activities, have been widely applied to deliver various therapeutic agents to synergistically combat the progression of malignant tumors. However, currently common inorganic nanozyme-based drug delivery systems still face challenges such as suboptimal biosafety, inadequate stability, and inferior tumor selectivity. Herein, a super-stable amino acid-based metallo-supramolecular nanoassembly (FPIC NPs) with peroxidase (POD)- and glutathione oxidase (GSHOx)-like activities was fabricated via Pt4+-driven coordination co-assembly of l-cysteine derivatives, the chemotherapeutic drug curcumin (Cur), and the photosensitizer indocyanine green (ICG). The superior POD- and GSHOx-like activities could not only catalyze the decomposition of endogenous hydrogen peroxide into massive hydroxyl radicals, but also deplete the overproduced glutathione (GSH) in cancer cells to weaken intracellular antioxidant defenses. Meanwhile, FPIC NPs would undergo degradation in response to GSH to specifically release Cur, causing efficient mitochondrial damage. In addition, FPIC NPs intrinsically enable fluorescence/photoacoustic imaging to visualize tumor accumulation of encapsulated ICG in real time, thereby determining an appropriate treatment time point for tumoricidal photothermal (PTT)/photodynamic therapy (PDT). In vitro and in vivo findings demonstrated the quadruple orchestration of catalytic therapy, chemotherapeutics, PTT, and PDT offers conspicuous antineoplastic effects with minimal side reactions. This work may provide novel ideas for designing supramolecular nanoassemblies with multiple enzymatic activities and therapeutic functions, allowing for wider applications of nanozymes and nanoassemblies in biomedicine.

Comparison of efficacy and safety between neoadjuvant chemotherapy and neoadjuvant immune checkpoint inhibitors combined with chemotherapy for locally advanced esophageal squamous cell carcinoma: a systematic review and meta-analysis.

BACKGROUND: The application of neoadjuvant immune checkpoint inhibitors combined with chemotherapy (NICT) in treating locally advanced oesophageal squamous cell carcinoma (ESCC) is a subject of considerable research interest. In light of this, we undertook a comprehensive meta-analysis aiming to compare the efficacy and safety of this novel approach with conventional neoadjuvant chemotherapy (NCT) in the management of ESCC. METHODS: A systematic search was conducted in PubMed, Embase, Cochrane Library, and Web of Science to gather relevant literature on the efficacy and safety of NICT compared to conventional NCT in locally advanced ESCC published before June 2023. Effect indicators, including odds ratios (ORs) with associated 95% CIs, were employed to evaluate the safety and efficacy outcomes. The risk of bias was assessed using the Cochrane bias risk assessment tool, and s ubgroup analysis and sensitivity analysis were conducted to investigate the findings further. RESULTS: A total of nine studies qualified for the meta-analysis, all of which investigated the efficacy and safety of NICT compared to conventional NCT. The pooled rates of pathologic complete response and major pathologic response in the NICT group were significantly higher compared to the NCT group, with values of 26.9% versus 8.3% ( P <0.00001) and 48.1% versus 24.6% ( P <0.00001), respectively. The ORs for achieving pathologic complete response and major pathologic response were 4.24 (95% CI, 2.84-6.32, I 2 =14%) and 3.30 (95% CI, 2.31-4.71, I 2 =0%), respectively, indicating a significant advantage for the NICT group. Regarding safety outcomes, the pooled incidences of treatment-related adverse events and serious adverse events in the NICT group were 64.4% and 11.5%, respectively, compared to 73.8% and 9.3% in the NCT group. However, there were no significant differences observed between the two groups in terms of treatment-related adverse events (OR=0.67, 95% CI, 0.29-1.54, P =0.35, I 2 =58%) or serious adverse events (OR=1.28, 95% CI, 0.69-2.36, P =0.43, I 2 =0%). Furthermore, no significant differences were found between the NICT and NCT groups regarding R0 resection rates, anastomotic leakage, pulmonary infection, and postoperative hoarseness. CONCLUSIONS: Neoadjuvant immune checkpoint inhibitors combined with chemotherapy demonstrate efficacy and safety in treating resectable oesophageal squamous cell carcinoma. Nevertheless, additional randomized trials are required to confirm the optimal treatment regimen.

Nomogram-based prediction model for survival of COVID-19 patients: A clinical study.

The study aim to construct an effective model for predicting the survival period of COVID-19 patients. METHODS: Clinical data of 386 COVID-19 patients were collected from December 2022 to January 2023. The patients were randomly divided into training and validation cohorts in a 7:3 ratio. LASSO regression and multivariate Cox regression analyses were used to identify prognostic factors, and a nomogram was constructed. Nomogram was evaluated using decision curve analysis, receiver operating characteristic curve, consistency index (c-index), and calibration curve. RESULTS: 86 patients (22.3%) died. A new nomogram for predicting the survival was established based on age, resting oxygen saturation, Blood urea nitrogen (BUN), c-reactive protein-to-albumin ratio (CAR), and pneumonia visual score. The decision curve indicated high clinical applicability. The nomogram c-indexes in the training and validation cohorts were 0.846 and 0.81, respectively. The area under the curves (AUCs) for the 15-day and 30-day survival probabilities were 0.906 and 0.869 in the training cohort, and 0.851 and 0.843 in the validation cohort. The calibration curves demonstrated consistency between predicted and actual survival probabilities. CONCLUSIONS: Our nomogram has the capacity to assist clinical practitioners in estimating the survival rate of COVID-19 patients, thereby facilitating more optimal management strategies and therapeutic interventions with substantial clinical applicability.

Glutathione/pH-responsive copper-based nanoplatform for amplified chemodynamic therapy through synergistic cycling regeneration of reactive oxygen species and dual glutathione depletion.

The rapid scavenging of reactive oxygen species (ROS) by glutathione (GSH) and insufficient endogenous hydrogen peroxide (H2O2) in tumor cells are the major factors greatly restricting the efficacy of chemodynamic therapy (CDT). Herein, we developed a tumor microenvironment (TME)-responsive Cu-based metal-mesoporous organosilica nanoplatform integrating vitamin k3 (VK3), which could deplete GSH and specifically regenerate H2O2 for amplified CDT of cancer. Once the CuO@MON-PEG/VK3 nanoparticles entered into the tumor cells through enhanced permeability and retention (EPR) effect, the organosilicon shell and CuO core would be successively degraded upon the triggering of GSH and endo/lysosomal acidity. Subsequently, the enriched tetrasulfide bridges and released Cu2+ could consume GSH substantially, thus triggering Fenton-like reaction for CDT. Furthermore, the released VK3 could be catalyzed by the highly expressed quinone oxidoreductase-1 (NQO1) inside tumor cells to generate sufficient H2O2 through a "reversible" redox cycle, which in turn promoted Cu+-mediated Fenton-like reaction. Both in vitro and in vivo studies demonstrated that this nanoplatform could achieve synergistic CDT against tumor through synergistic cycling regeneration of ROS and dual GSH exhaustion with excellent biosafety. Our finding highlight the promising potential of CuO@MON-PEG/VK3 nanoplatform with multiple oxidative stress amplification for highly efficient tumor therapy.

Additional neoadjuvant immunotherapy does not increase the risk of anastomotic leakage after esophagectomy for esophageal squamous cell carcinoma: a multicenter retrospective cohort study.

PURPOSE: Neoadjuvant chemoimmunotherapy (nICT) is a novel and promising therapy model for locally advanced esophageal squamous cell carcinoma.The objective of this study aimed to assessed the impact of additional neoadjuvant immunotherapy on patients' short-term outcomes, particularly the incidence of anastomotic leakage (AL) and pathological response. METHODS: Patients with locally advanced esophageal squamous cell carcinoma who received neoadjuvant chemotherapy (nCT)/ nICT combination with radical esophagectomy were enrolled from three medical centers in China. The authors used propensity score matching (PSM, ration:1:1, caliper=0.01) and inverse probability processing weighting (IPTW) to balance the baseline characteristics and compare the outcomes. Conditional logistic regression and weighted logistic regression analysis were used to further evaluate whether additional neoadjuvant immunotherapy would increase the risk of postoperative AL. RESULTS: A total of 331 patients getting partially advanced ESCC receiving nCT or nICT were enrolled from three medical centers in China. After PSM/IPTW, the baseline characteristics reached an equilibrium between the two groups. After matching, there were no significant difference in the AL incidence between the two groups ( P =0.68, after PSM; P =0.97 after IPTW), and the incidence of AL in the two groups was 15.85 versus 18.29%, and 14.79 versus 15.01%, respectively. After PSM/IPTW, both groups were similar in pleural effusion and pneumonia. After IPTW, the nICT group had a higher incidence of bleeding (3.36 vs. 0.30%, P =0.01), chylothorax (5.79 0.30%, P =0.001), and cardiac events (19.53 vs. 9.20%, P =0.04). recurrent laryngeal nerve palsy (7.85 vs. 0.54%, P =0.003). After PSM, both groups were similar in palsy of the recurrent laryngeal nerve (1.22 vs. 3.66%, P =0.31) and cardiac events (19.51 vs. 14.63%, P =0.41). Weighted logistic regression analysis showed that additional neoadjuvant immunotherapy was not responsible for AL (OR=0.56, 95% CI: [0.17, 1.71], after PSM; 0.74, 95% CI: [0.34,1.56], after IPTW). The nICT group had dramatically higher pCR in primary tumor than the nCT group ( P =0.003, PSM; P =0.005, IPTW), 9.76 versus 28.05% and 7.72 versus 21.17%, respectively. CONCLUSIONS: Additional neoadjuvant immunotherapy could benefit pathological reactions without increasing the risk of AL and pulmonary complications. The authors require further randomized controlled research to validate whether additional neoadjuvant immunotherapy would make a difference in other complications, and determine whether pathologic benefits could translate into prognostic benefits, which would require longer follow-up.

Bioengineered nanogenerator with sustainable reactive oxygen species storm for self-reinforcing sono-chemodynamic oncotherapy.

Oxidative stress-based antitumor modalities derived from reactive oxygen species (ROS) storms have attracted increasing attention. Nevertheless, low delivery efficiency, poor selectivity, hypoxia and overexpressed glutathione (GSH) have severely restricted the sustainable generation of the ROS storm in tumor cells. Herein, we design a bioengineered nanogenerator by coordination-driven co-assembly of sonosensitizer indocyanine green (ICG), Fenton-like agent copper ion (CuⅡ) and mitochondrial respiratory inhibitor metformin (MET), which is then camouflaged by a cancer cytomembrane to induce a sustainable intracellular ROS storm for on-demand self-reinforcing sono-chemodynamic oncotherapy. Such a nanogenerator with a core-shell structure, suitable diameter and outstanding stability can efficiently accumulate in tumor regions and then internalize into tumor cells through the camouflaging and homologous targeting strategy of the cancer cytomembrane. The nanogenerator shows an exceptional instability under the triple stimulations of acidic lysosomes, overexpressed GSH and ultrasound (US) radiation, thereby resulting in the rapid disassembly and burst drug release. Interestingly, the released MET significantly enhances the sonodynamic therapy (SDT) efficacy of the released ICG by inhibiting mitochondrial respiration and meanwhile the released CuⅡ obviously reduces ROS elimination by downregulating overexpressed GSH for self-amplifying and self-protecting the intracellular ROS storm. Moreover, such a nanogenerator almost completely achieves the tumor ablation in vivo in a single therapy cycle. Taken together, our bioengineered nanogenerator with a sustainable ROS storm can provide a promising strategy for ROS storm-based oncotherapy.

Efficacy and Safety of Neoadjuvant Chemoimmunotherapy in Resectable Esophageal Squamous Cell Carcinoma: A Meta-analysis.

PURPOSE: This study aimed to summarize the efficacy and safety of neoadjuvant chemoimmunotherapy in resectable esophageal squamous cell carcinoma (ESCC). METHODS: Literature focusing on the efficacy and safety of neoadjuvant immunotherapy or chemoimmunotherapy in resectable ESCC published before June 2022 was retrieved from PubMed, Embase, Cochrane Library, and Web of Science. The risk of bias was assessed using the Cochrane risk-of-bias assessment tool. Subgroup and sensitivity analyses were further performed. RESULTS: A total of 452 patients from 15 studies were included in this meta-analysis. All of the studies explored the efficacy and safety of neoadjuvant chemoimmunotherapy. The pooled major pathological response (MPR) rate and pathological complete response (PCR) rate were 58.3% and 32.9%, respectively. The pooled incidence of treatment-related adverse events (TRAEs) and serious adverse events (SAEs) were 91.6% and 19.4%, respectively. The pooled R0 resection rate was 92.8%, and the resection rate was 81.1%. Incidence of anastomotic leakage, pulmonary infection, and postoperative hoarseness were 10.7%, 21.3%, and 13.0%, respectively. Compared with 2 cycles of neoadjuvant therapy, patients who received > 2 cycles of neoadjuvant therapy showed higher MPR rate (57.3% vs. 61.1%) and PCR rate (30.6% vs. 37.9%), and the incidence of TRAEs (89.2% vs. 98.9%) tended to be higher. However, no significant difference was found (P > 0.05). Two cycles of neoadjuvant therapy showed higher R0 resection rate and resection rate (R0 resection rate: 96.0% vs. 87.8%, P = 0.02; resection rate: 85.6% vs. 74.7%, P = 0.01). Pembrolizumab- and tislelizumab-based neoadjuvant therapy showed higher MPR rate (72.4% and 72.2%) and PCR rate (41.5 % and 50.0%). Compared with other ICIs, tislelizumab-based neoadjuvant therapy showed lower R0 resection rate (80.5%). The pooled incidence of SAEs for pembrolizumab-based neoadjuvant therapy (2.0%) was lower. Camrelizumab-based neoadjuvant therapy showed lower incidence of pulmonary infection (11.5%). CONCLUSIONS: Neoadjuvant chemoimmunotherapy is effective and safe for resectable ESCC.

GSH-Responsive and Hypoxia-Activated Multifunctional Nanoparticles for Synergetically Enhanced Tumor Therapy.

The integration of reactive oxygen species (ROS)-based chemodynamic therapy (CDT) and photodynamic therapy (PDT) has attracted enormous attention for synergistic antitumor therapies. However, the strategy is severely hampered by tumor hypoxia and overproduced antioxidant glutathione (GSH) in the tumor microenvironment. Inspired by the concept of metal coordination-based nanomedicines, we proposed an effective strategy for synergistic cancer treatment in response to the special tumor microenvironmental properties. Herein, we present novel metal-coordinated multifunctional nanoparticles (NPs) by the Cu2+-triggered assembly of photosensitizer indocyanine green (ICG) and hypoxia-activated anticancer prodrug tirapazamine (TPZ) (Cu-ICG/TPZ NPs). After accumulating within tumor sites via the enhanced permeability and retention (EPR) effect, the Cu-ICG/TPZ NPs were capable of triggering a cascade of combinational therapeutic reactions, including hyperthermia, GSH elimination, and Cu+-mediated •OH generation and the subsequent hypoxia-triggered chemotherapeutic effect of TPZ, thus achieving synergistic tumor therapy. Both in vitro and in vivo evaluations suggested that the multifunctional Cu-ICG/TPZ NPs could realize satisfactory therapeutic efficacy with excellent biosafety. These results thus suggested the great potential of Cu-ICG/TPZ NPs to serve as a metallodrug nanoagent for synergetically enhanced tumor treatment.

Development of nomograms predictive of anastomotic leakage in patients before minimally invasive McKeown esophagectomy.

Purpose: The present study aims to identify factors related to anastomotic leakage before esophagectomy and to construct a prediction model. Methods: A retrospective analysis of 285 patients who underwent minimally invasive esophagectomy (MIE). An absolute shrinkage and selection operator was applied to screen the variables, and predictive models were developed using binary logistic regression. Results: A total of 28 variables were collected in this study. LASSO regression analysis, combined with previous literature and clinical experience, finally screened out four variables, including aortic calcification, heart disease, BMI, and FEV1. A binary logistic regression was conducted on the four predictors, and a prediction model was established. The prediction model showed good discrimination and calibration, with a C-statistic of 0.67 (95% CI, 0.593-0.743), a calibration curve fitting a 45° slope, and a Brier score of 0.179. The DCA demonstrated that the prediction nomogram was clinically useful. In the internal validation, the C-statistic still reaches 0.66, and the calibration curve has a good effect. Conclusions: When patients have aortic calcification, heart disease, obesity, and a low FEV1, the risk of anastomotic leakage is higher, and relevant surgical techniques can be used to prevent it. Therefore, the clinical prediction model is a practical tool to guide surgeons in the primary prevention of anastomotic leakage.

The development of a nomogram model for predicting left recurrent laryngeal nerve lymph node metastasis in esophageal cancer based on radiomics and clinical factors.

Background: The lymph node dissection for esophageal cancer is controversial. Some prediction models of lymph node metastasis (LNM) use the short diameter of lymph nodes measured by computed tomography (CT) examination as a predictor, but the size of that for judging metastasis is still controversial. However, radiomics can extract some features in tumors that cannot be obtained by naked eyes, which may have a higher value in predicting LNM. In this study, a nomogram was developed based on radiomics and clinical factors to predict left recurrent laryngeal nerve lymph node (RLNN) metastasis in patients with esophageal squamous cell carcinoma (ESCC). Methods: There were 350 patients included in this retrospective study. And the postoperative pathological results determined whether there was left RLNN metastasis. A univariate analysis was conducted of the clinical data. The least absolute shrinkage and selection operator regression analysis was conducted to filter the radiomics features extracted from CT images. The multivariate logistic regression equation was used to construct a nomogram. The area under the curve (AUC) was used to evaluate the predictive ability. Due to the small sample size, we chose to perform internal validation after the model was established by 10-fold cross-validation, Harrell's concordance index (C-index), bootstrap validation and calibration. Results: Ultimately, 3 indicators were screened out; that is, tumor location, surface volume ratio, and run-length non-uniformity. We then constructed the nomogram using these 3 indicators. The model had good accuracy and calibration performance. It has an AUC of 0.903 (95% confidence interval: 0.861-0.945), a sensitivity of 0.873, and a specificity of 0.756. Ten-fold cross-validation showed that the sensitivity and specificity of the training set were 88.08% and 75.81%, and the validation set had a sensitivity of 85.08% and a specificity of 75.49%. The Brier score was 0.074, and C-index was 0.904, which indicated good consistency between the actual and predicted results. Conclusions: A nomogram constructed based on radiomics features and clinical factors can be used to predict the metastasis of left RLNN in patients with ESCC in a non-invasive way, which provided a reference for clinicians to formulate individualized lymph node dissection plans.

"Watson-Crick G[triple bond, length as m-dash]C"-inspired supramolecular nanodrug of methotrexate and 5-fluorouracil for tumor microenvironment-activatable self-recognizing synergistic chemotherapy.

Carrier-free nanodrugs, generated via the straightforward small-molecule self-assembly of anticancer drugs, provide a promising route for cancer chemotherapy. However, their low structural stability, lack of targeting specificity, and poor stimulus responsiveness are still limiting their therapeutic effect. Inspired by Watson-Crick G[triple bond, length as m-dash]C base pairing, the FDA-approved chemo-drug methotrexate (MTX, which can bind with folate receptors) and 5-fluorouracil (5-FU, a DNA/RNA synthetase inhibitor) were adopted for direct assembly into self-recognizing MTX-5-FU nanoparticles via "Watson-Crick-like base pairing"-driven precise supramolecular assembly. Sequentially, our synthesized weak acidity-responsive polyethylene glycol (PEG) was inserted onto the nanoparticle surface to temporarily shield the self-targeting function of MTX and prolong the blood circulation time. Once PEG-MTX-5-FU nanoparticles reached the weakly acidic tumor microenvironment, the PEG corona could be cleaved from their surface and then MTX could be re-exposed to recover its self-recognition ability and significantly elevate tumor cell uptake; furthermore, the de-PEGylated MTX-5-FU nanoparticles could respond to the stronger acidity of lysosome, triggering core disassembly and thus the burst release of both MTX and 5-FU. Further in vitro and in vivo studies consistently confirmed that the nanodrugs exhibited preferable accumulation at the tumor sites with highly synergistic chemotherapeutic effects. The supramolecular recognition-inspired, cascade-triggered self-targeting and controlled release of nanodrugs could be a promising strategy to improve synergistic chemotherapy.

Regulation of Autophagy Orchestrates Pyroptotic Cell Death in Molybdenum Disulfide Quantum Dot-Induced Microglial Toxicity.

Molybdenum disulfide quantum dots (MoS2 QDs) represent an emerging class of two-dimensional (2D) atomically layered transition metal dichalcogenide nanostructures with few nanometers in lateral size, which show attractive potential as versatile platforms for theranostic applications in various neurological disorders. However, the potential impacts of MoS2 QDs on microglia remain unclear. In this report, we showed that exposure of microglia to MoS2 QDs triggered NLRP3 inflammasome activation as revealed by the cleavage of the inactive precursor of caspase-1 to its active form and the increased release of downstream pro-inflammatory cytokines, resulting in microglia cell death that occurred through caspase-1-dependent pyroptosis. We also found that MoS2 QDs activated autophagy, and suppression of autophagy by specific inhibitors potentiated MoS2 QD-induced pyroptosis. Additionally, MoS2 QDs stimulated mitochondria-derived reactive oxygen species (mtROS) generation in BV-2 cells. However, ROS scavengers could diminish the MoS2 QD-mediated NLRP3 inflammasome activation and pyroptotic cell death in microglia. Overall, our findings identified pyroptosis as a cellular response to MoS2 QD exposure in microglial cells, affording novel insights into the neurotoxicity of MoS2 QDs and facilitating the rational design and application of functional MoS2 QDs in neuroscience.

Molybdenum Disulfide Quantum Dots Attenuates Endothelial-to-Mesenchymal Transition by Activating TFEB-Mediated Lysosomal Biogenesis.

A defective lysosome-autophagy degradation pathway contributes to a variety of endothelial-to-mesenchymal transition (EndMT)-related cardiovascular diseases. Molybdenum disulfide quantum dots (MoS2 QDs) are nanoscale sizes in the planar dimensions and atomic structures of transition metal dichalcogenides (TMDs) materials with excellent physicochemical and biological properties, making them ideal for various biomedical applications. In this study, water-soluble MoS2 QDs with an average diameter of about 3.4 nm were synthesized by using a sulfuric acid-assisted ultrasonic method. The as-prepared MoS2 QDs exhibited low cytotoxicity of less than 100 µg/mL in both human umbilical vein endothelial cells and human coronary artery endothelial cells and showed novel biological properties to prevent EndMT and promote angiogenesis in vitro. We found that MoS2 QDs treatment-induced transcription factor (TFEB) mediated lysosomal biogenesis, which could cause autophagy activation. Importantly, using in vitro transforming growth factor (TGF)-ß-induced EndMT model, we demonstrated that the cardiovascular protective effect of MoS2 QDs against EndMT acted through triggering TFEB nucleus translocation and restoring an impairment of autophagic flux, whereas genetic suppression of TFEB impaired the protective action of MoS2 QDs against EndMT. Taken together, these results gain novel insights into the mechanisms by which MoS2 QDs regulate EndMT and facilitate the development of MoS2-based nanoagents for the treatment of EndMT-related cardiovascular diseases.

Molybdenum Disulfide Nanoparticles Resist Oxidative Stress-Mediated Impairment of Autophagic Flux and Mitigate Endothelial Cell Senescence and Angiogenic Dysfunctions.

The impairment of autophagy involves oxidative stress-induced cellular senescence, leading to endothelial dysfunctions and the onset of cardiovascular diseases. As molybdenum disulfide nanoparticles (MoS2 NPs), representative transition metal dichacogenide materials, have great potential as a multifunctional therapeutic agent against various disorders, the present study aimed to investigate whether MoS2 NPs prevents hydrogen peroxide (H2O2)-induced endothelial senescence by modulating autophagic process. Our results showed that pretreatment with MoS2 NPs inhibited H2O2-induced endothelial senescence and improved endothelial functions. Exposure of H2O2 increased p62 level and blocked the fusion of autophagosomes with lysosomes, indicating of impaired autophagic flux in senescent endothelial cells. However, MoS2 NPs pretreatment efficiently suppressed cellular senescence through triggering autophagy and resisting impaired autophagic flux. Furthermore, the genetic inhibition of autophagy by siRNA against Beclin 1 or ATG-5 directly abrogated the protective action of MoS2 NPs on endothelial cells against H2O2-induced senescence.Thus, these results suggested that MoS2 NPs rescue endothelial cells from H2O2-induced senescence by improving autophagic flux, and provide valuable information for the rational design of MoS2-based nanomaterials for therapeutic use in senescence-related diseases.

Gold nanoparticles enhance TRAIL sensitivity through Drp1-mediated apoptotic and autophagic mitochondrial fission in NSCLC cells.

Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its agonistic receptors have been identified as highly promising antitumor agents preferentially eliminating cancer cells with minimal damage, the emergence of TRAIL resistance in most cancers may contribute to therapeutic failure. Thus, there is an urgent need for new approaches to overcome TRAIL resistance. Gold nanoparticles (AuNPs) are one of the most promising nanomaterials that show immense antitumor potential via targeting various cellular and molecular processes; however, the effects of AuNPs on TRAIL sensitivity in cancer cells remain unclear. In this study, we found that AuNPs combined with TRAIL exhibited a greater potency in promoting apoptosis in non-small-cell lung cancer (NSCLC) cells compared with TRAIL alone, suggesting that AuNPs sensitize cancer cells to TRAIL. Further experiments demonstrated that the combination of TRAIL and AuNPs was more effective in causing excessive mitochondrial fragmentation in cancer cells accompanied by a dramatic increase in mitochondrial recruitment of dynamin-related protein 1 (Drp1), mitochondrial dysfunctions, and enhancement of autophagy induction. Small interfering RNA (siRNA) silencing of Drp1 or inhibition of autophagy could effectively alleviate apoptosis in cells exposed to TRAIL combined with AuNPs. In vivo studies revealed that AuNPs augmented TRAIL sensitivity in tumor-bearing mice. Our data indicated that AuNPs potentiate apoptotic response to TRAIL in NSCLC cells through Drp1-dependent mitochondrial fission, and TRAIL combined with AuNPs can be a potential chemotherapeutic strategy for the treatment of NSCLC.