Long-acting bulleyaconitine A microspheres via intra-articular delivery for multidimensional therapy of rheumatoid arthritis.

Bulleyaconitine A (BLA) is a promising candidate for treating rheumatoid arthritis (RA) with diverse pharmacological activities, including anti-inflammatory, analgesic and bone repair. Herein, the long-acting bulleyaconitine A microspheres (BLA-MS) were developed to treat RA comprehensively by forming drug reservoirs in joint cavities. The BLA-MS were prepared by emulsion/solvent evaporation method. The particle size and distribution were assessed by SEM. The crystalline state was investigated by DSC and PXRD. The drug loading (DL), encapsulation efficiency (EE) and cumulative release in vitro were determined by HPLC. The DL and EE were 23.93 ±â€¯0.38 % and 95.73 ±â€¯1.56 % respectively, and the cumulative release was up to 69 days with a stable release curve. The pharmacodynamic results in collagen induced arthritis (CIA) rats showed a noticeable reduction in paw thickness (5.66 ±â€¯0.32 mm), and the decreasing expression level of PGE2, TNF-α and IL-6 which diminished the infiltration of inflammatory cells, thereby alleviating the progression of erosion and repairing the damaged bones (BV/TV (Bone Volume / Total Volume): 81.97 %, BS/BV (Bone Surface / Bone Volume): 6.08 mm-1). In conclusion, intra-articular injection of BLA-MS should have a promising application in the treatment of RA and may achieve clinical transformation in the future.

Glucocorticoids-based prodrug design: Current strategies and research progress.

Attributing to their broad pharmacological effects encompassing anti-inflammation, antitoxin, and immunosuppression, glucocorticoids (GCs) are extensively utilized in the clinic for the treatment of diverse diseases such as lupus erythematosus, nephritis, arthritis, ulcerative colitis, asthma, keratitis, macular edema, and leukemia. However, long-term use often causes undesirable side effects, including metabolic disorders-induced Cushing's syndrome (buffalo back, full moon face, hyperglycemia, etc.), osteoporosis, aggravated infection, psychosis, glaucoma, and cataract. These notorious side effects seriously compromise patients' quality of life, especially in patients with chronic diseases. Therefore, glucocorticoid-based advanced drug delivery systems for reducing adverse effects have received extensive attention. Among them, prodrugs have the advantages of low investment, low risk, and high success rate, making them a promising strategy. In this review, we propose the strategies for the design and summarize current research progress of glucocorticoid-based prodrugs in recent decades, including polymer-based prodrugs, dendrimer-based prodrugs, antibody-drug conjugates, peptide-drug conjugates, carbohydrate-based prodrugs, aliphatic acid-based prodrugs and so on. Besides, we also raise issues that need to be focused on during the development of glucocorticoid-based prodrugs. This review is expected to be helpful for the research and development of novel GCs and prodrugs.

Research on the loading and release kinetics of the vincristine sulfate liposomes and its anti-breast cancer activity.

Vincristine (VCR), as a cytotoxic drug, is used clinically to treat acute lymphatic leukemia and breast cancer, and commonly used clinically as vincristine sulfate (VCRS). However, its clinical use is limited by unpredictable pharmacologic characteristics, a narrow therapeutic index, and neurotoxicity. The pH gradient method was used for active drug loading of VCRS, and the process route mainly includes the preparation of blank liposomes and drug-loaded liposomes. VCRS liposomes had suitable particle size, high encapsulation efficiency and good stability. The loading and release kinetics of VCRS liposomes were explored. By calculating the changes of encapsulation efficiency with time at different temperatures, it was confirmed that the drug-loading process of liposomes exhibited a first-order kinetic feature, and the activation energy required for the reaction was determined as 20.6 kcal/mol. The release behavior at different pH was also investigated, and it was demonstrated that the release behavior conformed to the first-order model, suggesting that the release mechanism of VCRS was simple transmembrane diffusion. VCRS liposomes also enhanced in vitro and in vivo antitumor activity. Thus, VCRS liposomes showed great potential for VCRS delivery, and the loading and release kinetics were well researched to provide a reference for investigating active drug loading liposomes.

Effect of mPEG-PLGA on Drug Crystallinity and Release of Long-Acting Injection Microspheres: In Vitro and In Vivo Perspectives.

PURPOSE: Traditional progesterone (PRG) injections require long-term administration, leading to poor patient compliance. The emergence of long-acting injectable microspheres extends the release period to several days or even months. However, these microspheres often face challenges such as burst release and incomplete drug release. This study aims to regulate drug release by altering the crystallinity of the drug during the release process from the microspheres. METHODS: This research incorporates methoxy poly(ethylene glycol)-b-poly(lactide-co-glycolide) (mPEG-PLGA) into poly(lactide-co-glycolide) (PLGA) microspheres to enhance their hydrophilicity, thus regulating the release rate and drug morphology during release. This modification aims to address the issues of burst and incomplete release in traditional PLGA microspheres. PRG was used as the model drug. PRG/mPEG-PLGA/PLGA microspheres (PmPPMs) were prepared via an emulsification-solvent evaporation method. Scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), and differential scanning calorimetry (DSC) were employed to investigate the presence of PRG in PmPPMs and its physical state changes during release. RESULTS: The addition of mPEG-PLGA altered the crystallinity of the drug within the microspheres at different release stages. The crystallinity correlated positively with the amount of mPEG-PLGA incorporated; the greater the amount, the faster the drug release from the formulation. The bioavailability and muscular irritation of the long-acting injectable were assessed through pharmacokinetic and muscle irritation studies in Sprague-Dawley (SD) rats. The results indicated that PmPPMs containing mPEG-PLGA achieved low burst release and sustained release over 7 days, with minimal irritation and self-healing within this period. PmPPMs with 5% mPEG-PLGA showed a relative bioavailability (Frel) of 146.88%. IN CONCLUSION: In summary, adding an appropriate amount of mPEG to PLGA microspheres can alter the drug release process and enhance bioavailability.

Aberrant angiogenic signaling pathways: Accomplices in ovarian cancer progression and treatment.

Ovarian cancer is one of the most common malignant tumors in women, and treatment options are limited. Despite efforts to adjust cancer treatment models and develop new methods, including tumor microenvironment (TME) therapy, more theoretical support is needed. Increasing attention is being given to antiangiogenic measures for TME treatment. Another important concept in ovarian cancer TME is angiogenesis, where tumor cells obtain nutrients and oxygen from surrounding tissues through blood vessels to support further expansion and metastasis. Many neovascularization signaling pathways become imbalanced and hyperactive during this process. Inhibiting these abnormal pathways can yield ideal therapeutic effects in patients, even by reversing drug resistance. However, these deep TME signaling pathways often exhibit crosstalk and correlation. Understanding these interactions may be an important strategy for further treating ovarian cancer. This review summarizes the latest progress and therapeutic strategies for these angiogenic signaling pathways in ovarian cancer.

Dual-Targeted Self-Adjuvant Heterocyclic Lipidoid@Polyester Hybrid Nanovaccines for Boosting Cancer Immunotherapy.

Tumor vaccines have demonstrated a modest response rate, primarily attributed to their inefficient delivery to dendritic cells (DCs), low cross-presentation, DC-intrinsic immunosuppressive signals, and an immunosuppressive tumor microenvironment (TME). Here, draining lymph node (DLN)-targeted and tumor-targeted nanovaccines were proposed to address these limitations, and heterocyclic lipidoid (A18) and polyester (BR647) were synthesized to achieve dual-targeted cancer immunotherapy. Meanwhile, oligo hyaluronic acid (HA) and DMG-PEG2000-Mannose were incorporated to prepare dual-targeted nanovaccines encapsulated with STAT3 siRNA and model antigens. The nanovaccines were designed to target the DLN and the tumor, facilitating the delivery of cargo into the cytoplasm. These dual-targeted nanovaccines improved antigen presentation and DC maturation, activated the stimulator of interferon genes (STING) pathway, enhanced the pro-apoptotic effect, and stimulated antitumor immune responses. Additionally, these dual-targeted nanovaccines overcame immunosuppressive TME, reduced immunosuppressive cells, and promoted the polarization of tumor-associated neutrophils from N2 to N1. Among the four dual-targeted nanovaccines that induced robust antitumor responses, the heterocyclic lipidoid@polyester hybrid nanovaccines (MALO@HBNS) demonstrated the most promising results. Furthermore, a combination strategy involving MALO@HBNS and an anti-PD-L1 antibody exhibited an immensely powerful anticancer role. This work introduced a dual-targeted nanovaccine platform for antitumor treatment, suggesting its potential combination with an immune checkpoint blockade as a comprehensive anticancer strategy.

Enhanced localized therapeutic precision: A face-to-face folate-targeted Cu2+-mediated nanotherapy with thermosensitive sustained-release system.

Safe and effective Cu2+ supplementation in local lesion is crucial for minimizing toxicity of DSF-based chemotherapy. Targeted delivery of Cu2+ appears more promising. Intraperitoneal chemotherapy for peritoneal carcinoma (PC) establishes "face-to-face" contact between targeted nanocarriers and tumor tissue. Herein, this study developed a biodegradable, injectable thermosensitive hydrogel that coencapsulating DSF submicroemulsion (DSF-SE) and folate-modified liposome loading glycyrrhizic acid-Cu (FCDL). FCDL acted as 'beneficial horse' to target the tumor-localized folate receptor, thus liberating Cu2+ in tumor nidus. The prepared FCDL and DSF-SE were found with uniform sizes (160.2 nm, 175.4 nm), low surface charge (-25.77 mV, -16.40 mV) and high encapsulation efficiency (97.93 %, 90.08 %). In vitro drug release profile of FCDL, DSF-SE and FCDL＆DSF-SE@G followed a sustained release pattern. And the release behavior of Cu2+ from FCDL was pH-related, i.e., Cu2+ was released faster under acidic condition. When FCDL and DSF-SE were loaded into an PLGA-PEG-PLGA-based hydrogel system, FCDL＆DSF-SE@G was formed to ensure separated delivery of Cu2+ and DSF in space but synchronized release over time. The rheology experiment showed a satisfactory gelling temperature of 32.7 °C. In vitro cytotoxicity study demonstrated that FCDL＆DSF-SE@G significantly lowered the IC50 of free Cu2+/DSF, Cu2+/DSF hydrogel and non-targeted analogue by almost 70 %, 65 % and 32 %, respectively. Accordingly, in tumor-bearing mice, FCDL＆DSF-SE@G augmented the tumor inhibition rates for the same formulations by 352 %, 145 % and 44 %, respectively. The main mechanism was attributed to higher uptake of FCDL and DSF-SE, resulting in increased Cu(DDTC)2 formation, ROS production and cell apoptosis. In conclusion, this targeted nanotherapy approach with dual-nanocarriers loaded hydrogel system, with its focus on face-to-face contact between nanocarriers and tumor tissues in the peritoneal cavity, holds significant promise for intraperitoneal chemotherapy in PC.

Eudragit L100-coated nintedanib nanocrystals improve oral bioavailability by reducing drug particle size and maintaining drug supersaturation.

The aim of this study was to prepare nintedanib nanocrystals (BIBF-NCs) to lower the solubility of the drug in the stomach, maintain the supersaturation of the drug in the intestine, and improve the oral absorption of nintedanib (BIBF). In this study, BIBF-NCs were prepared by acid solubilization and alkaline precipitation following nano granding method, with a particle size of 290.80 nm and a zeta potential of -49.13 mV. Subsequently, Nintedanib enteric-coated nanocrystals (BIBF-NCs@L100) were obtained by coating with Eudragit L100. The microscopic morphology, crystalline characteristics, stability, and in vitro dissolution of BIBF-NCs and BIBF-NCs@L100 were also studied. In addition, the in vivo pharmacokinetic behaviors of Samples prepared according to the prescription process of commercially available soft capsules (soft capsules), BIBF-NCs, and BIBF-NCs@L100 were further investigated. The results showed that the oral bioavailability of BIBF-NCs and BIBF-NCs@L100 were increased by 1.43 and 2.58 times, compared with that of the soft capsules. BIBF-NCs@L100 effectively reduced the release of BIBF in the formulation in the stomach, allowing more drug to reach the intestine in the form of nanocrystals, maintaining the supersaturation in the intestine, thereby improving the oral bioavailability of the drug.

ESM1 enhances fatty acid synthesis and vascular mimicry in ovarian cancer by utilizing the PKM2-dependent warburg effect within the hypoxic tumor microenvironment.

BACKGROUND: The hypoxic tumor microenvironment is a key factor that promotes metabolic reprogramming and vascular mimicry (VM) in ovarian cancer (OC) patients. ESM1, a secreted protein, plays an important role in promoting proliferation and angiogenesis in OC. However, the role of ESM1 in metabolic reprogramming and VM in the hypoxic microenvironment in OC patients has not been determined. METHODS: Liquid chromatography coupled with tandem MS was used to analyze CAOV3 and OV90 cells. Interactions between ESM1, PKM2, UBA2, and SUMO1 were detected by GST pull-down, Co-IP, and molecular docking. The effects of the ESM1-PKM2 axis on cell glucose metabolism were analyzed based on an ECAR experiment. The biological effects of the signaling axis on OC cells were detected by tubule formation, transwell assay, RT‒PCR, Western blot, immunofluorescence, and in vivo xenograft tumor experiments. RESULTS: Our findings demonstrated that hypoxia induces the upregulation of ESM1 expression through the transcription of HIF-1α. ESM1 serves as a crucial mediator of the interaction between PKM2 and UBA2, facilitating the SUMOylation of PKM2 and the subsequent formation of PKM2 dimers. This process promotes the Warburg effect and facilitates the nuclear translocation of PKM2, ultimately leading to the phosphorylation of STAT3. These molecular events contribute to the promotion of ovarian cancer glycolysis and vasculogenic mimicry. Furthermore, our study revealed that Shikonin effectively inhibits the molecular interaction between ESM1 and PKM2, consequently preventing the formation of PKM2 dimers and thereby inhibiting ovarian cancer glycolysis, fatty acid synthesis and vasculogenic mimicry. CONCLUSION: Our findings demonstrated that hypoxia increases ESM1 expression through the transcriptional regulation of HIF-1α to induce dimerization via PKM2 SUMOylation, which promotes the OC Warburg effect and VM.

An adaptive drug-releasing contact lens for personalized treatment of ocular infections and injuries.

This research introduces an innovative solution to address the challenges of bacterial keratitis and alkali burns. Current treatments for bacterial keratitis and alkali burns rely on the frequent use of antibiotics and anti-inflammatory eye drops. However, these approaches suffer from poor bioavailability and fluctuating concentrations, leading to limited efficacy and potential drug resistance. Our approach presents an adaptive drug-releasing contact lens responsive to reactive oxygen species (ROS) at ocular inflammation sites, synchronously releasing Levofloxacin and Diclofenac. During storage, minimal drug release occurred, but over 7 days of wear, the lens maintained a continuous, customizable drug release rate based on disease severity. This contact lens had strong antibacterial activity and biofilm prevention, effectively treating bacterial keratitis. When combined with autologous serum, this hydrophilic, flexible lens aids corneal epithelial regeneration, reducing irritation and promoting healing. In summary, this ROS-responsive drug-releasing contact lens combines antibacterial and anti-inflammatory effects, offering a promising solution for bacterial keratitis and alkali burns.

Effect of hydroxyethyl starch on drug stability and release of semaglutide in PLGA microspheres.

The degradation of peptide drugs limits the application of peptide drug microspheres. Structural changes of peptides at the water-oil interface and the destruction of their spatial structure in the complex microenvironment during polymer degradation can affect drug release and in vivo biological activity. This study demonstrates that adding hydroxyethyl starch (HES) to the internal aqueous phase (W1) significantly enhances the stability of semaglutide and optimizes its release behavior in PLGA microspheres. The results showed that this improvement was due to a spontaneous exothermic reaction (ΔH = -132.20 kJ mol-1) facilitated by hydrogen bonds. Incorporating HES into the internal aqueous phase using the water-in-oil-in-water (W1/O/W2) emulsion method yielded PLGA microspheres with a high encapsulation rate of 94.38 %. Moreover, microspheres with HES demonstrated well-controlled drug release over 44 days, unlike the slower and incomplete release in microspheres without HES. The optimized h-MG2 formulation achieved a more complete drug release (83.23 %) and prevented 30.65 % of drug loss compared to the HES-free microspheres within the same period. Additionally, the optimized semaglutide microspheres provided nearly three weeks of glycemic control with adequate safety. In conclusion, adding HES to the internal aqueous phase improved the in-situ drug stability and release behavior of semaglutide-loaded PLGA microspheres, effectively increasing the peptide drug payload in PLGA microspheres.

Distribution, Ecological Risk, and Source Identification of Heavy Metal(loid)s in Sediments of a Headwater of Beijiang River Affected by Mining in Southern China.

In this study, the contents of eight heavy metal(loid)s (As, Pb, Zn, Cd, Cr, Cu, Sb and Tl) in 50 sediment samples from a headwater of Beijiang River were studied to understand their pollution, ecological risk and potential sources. Evaluation indexes including sediment quality guidelines (SDGs), enrichment factor (EF), geo-accumulation index (Igeo), risk assessment code (RAC) and bioavailable metal index (BMI) were used to evaluate the heavy metal(loid)s pollution and ecological risk in the sediments. Pearson's correlation analysis and principal component analysis were used to identify the sources of heavy metal(loid)s. The results showed that the average concentration of heavy metal(loid)s obviously exceeded the background values, except Cr. Metal(loid)s speciation analysis indicated that Cd, Pb, Cu and Zn were dominated by non-residual fractions, which presented higher bioavailability. The S content in sediments could significantly influence the geochemical fractions of heavy metal(loid)s. As was expected, it had the most adverse biological effect to local aquatic organism, followed by Pb. The EF results demonstrated that As was the most enriched, while Cr showed no enrichment in the sediments. The assessment of Igeo suggested that Cd and As were the most serious threats to the river system, while Cr showed almost no contamination in the sediments. Heavy metal(loid)s in sediments in the mining- and smelting-affected area showed higher bioavailability. According to the results of the above research, the mining activities caused heavier heavy metal(loid)s pollution in the river sediment. Three potential sources of heavy metal(loid)s in sediment were distinguished based on the Pearson's correlation analysis and PCA, of which Cd, Pb, As, Zn, Sb and Cu were mainly derived from mining activities, Cr was mainly derived from natural sources, Tl was mainly derived from smelting activities.

Novel solid self-emulsifying drug delivery system to enhance oral bioavailability of cabazitaxel.

In this study, a novel cabazitaxel solid self-emulsifying drug delivery system (CTX S-SEDDS) was developed by solvent evaporation and liquid-solid compression technology, which overcame the limitations of the traditional SEDDS and improved the oral bioavailability. From the results of solubility, pseudo-ternary phase diagram, and single-factor analysis, Tween 80 (surfactant), Tricaprylin (oil), and Glyceryl monooleate (oil) with the ratio of 30:55:15 showed optimized particle size (140.87 nm), short emulsification and high cabazitaxel (CTX) loading capacity (50 mg·g-1). Based on the liquid-solid compression mathematical model, Syloid XDP3050 was determined as carrier material and Syloid 244FP as coating material. The prepared CTX S-SEDDS showed excellent flowability, tabletability, and reconstitution property. In vivo pharmacokinetics in rats demonstrated the absolute bioavailability of CTX S-SEDDS (17.27 %) was significantly enhanced compared with CTX solution (1.69 %), which was close to that of CTX-SEDSS (20.48 %). Lymphatic absorption was verified by in vitro imaging to be an important absorption route for self-emulsifying preparations. These results suggested that CTX S-SEDDS could enhance oral bioavailability of poorly water-soluble drug cabazitaxel while avoiding SEDDS limitations and harnessing the dual advantages of solid and liquid preparations.

LC-AMP-F1 Derived from the Venom of the Wolf Spider Lycosa coelestis, Exhibits Antimicrobial and Antibiofilm Activities.

In recent years, there has been a growing interest in antimicrobial peptides as innovative antimicrobial agents for combating drug-resistant bacterial infections, particularly in the fields of biofilm control and eradication. In the present study, a novel cationic antimicrobial peptide, named LC-AMP-F1, was derived from the cDNA library of the Lycosa coelestis venom gland. The sequence, physicochemical properties and secondary structure of LC-AMP-F1 were predicted and studied. LC-AMP-F1 was tested for stability, cytotoxicity, drug resistance, antibacterial activity, and antibiofilm activity in vitro compared with melittin, a well-studied antimicrobial peptide. The findings indicated that LC-AMP-F1 exhibited inhibitory effects on the growth of various bacteria, including five strains of multidrug-resistant bacteria commonly found in clinical settings. Additionally, LC-AMP-F1 demonstrated effective inhibition of biofilm formation and disruption of mature biofilms. Furthermore, LC-AMP-F1 exhibited favorable stability, minimal hemolytic activity, and low toxicity towards different types of eukaryotic cells. Also, it was found that the combination of LC-AMP-F1 with conventional antibiotics exhibited either synergistic or additive therapeutic benefits. Concerning the antibacterial mechanism, scanning electron microscopy and SYTOX Green staining results showed that LC-AMP-F1 increased cell membrane permeability and swiftly disrupted bacterial cell membranes to exert its antibacterial effects. In summary, the findings and studies facilitated the development and clinical application of novel antimicrobial agents.

Enhancing bank marketing strategies with ensemble learning: Empirical analysis.

In order to enhance market share and competitiveness, large banks are increasingly focusing on promoting marketing strategies. However, the traditional bank marketing strategy often leads to the homogenization of customer demand, making it challenging to distinguish among various products. To address this issue, this paper presents a customer demand learning model based on financial datasets and optimizes the distribution model of bank big data channels through induction to rectify the imbalance in bank customer transaction data. By comparing the prediction models of random forest model and support vector machine (SVM), this paper analyzes the ability of the prediction model based on ensemble learning to significantly enhance the market segmentation of e-commerce banks. The empirical results reveal that the accuracy of random forest model reaches 92%, while the accuracy of SVM model reaches 87%. This indicates that the ensemble learning model has higher accuracy and forecasting ability than the single model. It enables the bank marketing system to implement targeted marketing, effectively maintain the relationship between customers and banks, and significantly improve the success probability of product marketing. Meanwhile, the marketing model based on ensemble learning has achieved a sales growth rate of 20% and improved customer satisfaction by 30%. This demonstrates that the implementation of the ensemble learning model has also significantly elevated the overall marketing level of bank e-commerce services. Therefore, this paper offers valuable academic guidance for bank marketing decision-making and holds important academic and practical significance in predicting bank customer demand and optimizing product marketing strategy.

Intramuscular injection of palmitic acid-conjugated Exendin-4 loaded multivesicular liposomes for long-acting and improving in-situ stability.

BACKGROUND: Exendin-4 (Ex4) is a promising drug for diabetes mellitus with a half-life of 2.4 h in human bodies. Besides, the Ex4 formulations currently employed in the clinic or under development have problems pertaining to stability. In this study, palmitic acid-modified Ex4 (Pal-Ex4) was prepared and purified to extend the half-life of Ex4. In addition, Pal-Ex4-MVLs were further designed and optimized as a long-acting delivery system for intramuscular injection. METHODS: Pal-Ex4 was encapsulated within multivesicular liposomes (MVLs) via a two-step double emulsification process. The formulated products were then assessed for their vesicle size, encapsulation efficiency, and in vitro and in vivo. RESULTS: Pal-Ex4-MVLs with a notable encapsulation efficiency of 99.18% were successfully prepared. Pal-Ex4-MVLs, administered via a single intramuscular injection in Sprague-Dawley rats, sustained stable plasma concentrations for 168 h, presenting extended half-life (77.28 ± 12.919 h) and enhanced relative bioavailability (664.18%). MVLs protected Ex4 through providing stable retention and slow release. This approach considerably improved the in-situ stability of the drug for intramuscular administration. CONCLUSIONS: The combination of palmitic acid modification process with MVLs provides dual protection for Ex4 and can be a promising strategy for other hydrophilic protein/polypeptide-loaded sustained-release delivery systems with high drug bioactivity.

Genome-wide analyses reveal the contribution of somatic variants to the immune landscape of multiple cancer types.

It has been well established that cancer cells can evade immune surveillance by mutating themselves. Understanding genetic alterations in cancer cells that contribute to immune regulation could lead to better immunotherapy patient stratification and identification of novel immune-oncology (IO) targets. In this report, we describe our effort of genome-wide association analyses across 22 TCGA cancer types to explore the associations between genetic alterations in cancer cells and 74 immune traits. Results showed that the tumor microenvironment (TME) is shaped by different gene mutations in different cancer types. Out of the key genes that drive multiple immune traits, top hit KEAP1 in lung adenocarcinoma (LUAD) was selected for validation. It was found that KEAP1 mutations can explain more than 10% of the variance for multiple immune traits in LUAD. Using public scRNA-seq data, further analysis confirmed that KEAP1 mutations activate the NRF2 pathway and promote a suppressive TME. The activation of the NRF2 pathway is negatively correlated with lower T cell infiltration and higher T cell exhaustion. Meanwhile, several immune check point genes, such as CD274 (PD-L1), are highly expressed in NRF2-activated cancer cells. By integrating multiple RNA-seq data, a NRF2 gene signature was curated, which predicts anti-PD1 therapy response better than CD274 gene alone in a mixed cohort of different subtypes of non-small cell lung cancer (NSCLC) including LUAD, highlighting the important role of KEAP1-NRF2 axis in shaping the TME in NSCLC. Finally, a list of overexpressed ligands in NRF2 pathway activated cancer cells were identified and could potentially be targeted for TME remodeling in LUAD.

Activate the endogenous Cu2+ switch for Zn(DDC)2 liposomes conversion: Providing a safer and less toxic alternative in cancer therapy.

The ancient anti-alcohol drug disulfiram (DSF) has gained widespread attention for its highly effective anti-tumor effects in cancer treatment. Our previous studies have developed liposome of Cu (DDC)2 to overcome the limitations, like the poor water solubility. However, Cu (DDC)2 liposomes still have shown difficulties in severe hemolytic reactions at high doses and systemic toxicity, which have limited their clinical use. Therefore, this study aims to exploratively investigate the feasibility of using DSF or DDC in combination also can chelate Zn2+ to form zinc diethyldithiocarbamate (Zn (DDC)2). Furthermore, this study prepared stable and homogeneous Zn (DDC)2 liposomes, which were able to be released in the tumor microenvironment (TME). The released Zn (DDC)2 was converted to Cu (DDC)2 with the help of endogenous Cu2+-switch enriched in the TME, which has a higher stability constant compared with Zn (DDC)2. In other words, the Cu2+-switch is activated at the tumor site, completing the conversion of the less cytotoxic Zn (DDC)2 to the more cytotoxic Cu (DDC)2 for effective tumor therapy so that the Zn (DDC)2 liposomes in vivo achieved the comparable therapeutic efficacy and provided a safer alternative to Cu (DDC)2 liposomes in cancer therapy.

Deep Citywide Multisource Data Fusion-Based Air Quality Estimation.

With the increasingly serious air pollution, people are paying more and more attention to air quality. However, air quality information is not available for all regions, as the number of air quality monitoring stations in a city is limited. Existing air quality estimation methods only consider the multisource data of partial regions and separately estimate the air qualities of all regions. In this article, we propose a deep citywide multisource data fusion-based air quality estimation (FAIRY) method. FAIRY considers the citywide multisource data and estimates the air qualities of all regions at a time. Specifically, FAIRY constructs images from the citywide multisource data (i.e., meteorology, traffic, factory air pollutant emission, point of interest, and air quality) and uses SegNet to learn the multiresolution features from these images. The features with the same resolution are fused by the self-attention mechanism to provide multisource feature interactions. To get a complete air quality image with high resolution, FAIRY refines low-resolution fused features by employing high-resolution fused features through residual connections. In addition, the Tobler's first law of geography is used to constrain the air qualities of adjacent regions, which can fully use the air quality relevance of nearby regions. Extensive experimental results demonstrate that FAIRY achieves the state-of-the-art performance on the Hangzhou city dataset, outperforming the best baseline by 15.7% on MAE.

NDP52 SUMOylation contributes to low-dose X-rays-induced cardiac hypertrophy through PINK1/Parkin-mediated mitophagy via MUL1/SUMO2 signalling.

Radiation-induced heart damage caused by low-dose X-rays has a significant impact on tumour patients' prognosis, with cardiac hypertrophy being the most severe noncarcinogenic adverse effect. Our previous study demonstrated that mitophagy activation promoted cardiac hypertrophy, but the underlying mechanisms remained unclear. In the present study, PARL-IN-1 enhanced excessive hypertrophy of cardiomyocytes and exacerbated mitochondrial damage. Isobaric tags for relative and absolute quantification-based quantitative proteomics identified NDP52 as a crucial target mediating cardiac hypertrophy induced by low-dose X-rays. SUMOylation proteomics revealed that the SUMO E3 ligase MUL1 facilitated NDP52 SUMOylation through SUMO2. Co-IP coupled with LC-MS/MS identified a critical lysine residue at position 262 of NDP52 as the key site for SUMO2-mediated SUMOylation of NDP52. The point mutation plasmid NDP52K262R inhibited mitophagy under MUL1 overexpression, as evidenced by inhibition of LC3 interaction with NDP52, PINK1 and LAMP2A. A mitochondrial dissociation study revealed that NDP52K262R inhibited PINK1 targeting to endosomes early endosomal marker (EEA1), late/lysosome endosomal marker (LAMP2A) and recycling endosomal marker (RAB11), and laser confocal microscopy confirmed that NDP52K262R impaired the recruitment of mitochondria to the autophagic pathway through EEA1/RAB11 and ATG3, ATG5, ATG16L1 and STX17, but did not affect mitochondrial delivery to lysosomes via LAMP2A for degradation. In conclusion, our findings suggest that MUL1-mediated SUMOylation of NDP52 plays a crucial role in regulating mitophagy in the context of low-dose X-ray-induced cardiac hypertrophy. Two hundred sixty-second lysine of NDP52 is identified as a key SUMOylation site for low-dose X-ray promoting mitophagy activation and cardiac hypertrophy. Collectively, this study provides novel implications for the development of therapeutic strategies aimed at preventing the progression of cardiac hypertrophy induced by low-dose X-rays.