A new antibacterial with anti-inflammatory properties promotes wound healing through inhibiting cGAS/STING/NF-κB/IRF3 pathway.

Benzothiazole-urea hybrid 8l was found to be a potent anti-bacterial agent against methicillin-resistant Staphylococcus aureus (MRSA2858) (MIC = 0.78 µM, Eur J Med Chem. 2022,236:114333). Herein, 8l was further evaluated to remedy the MRSA-infected scald with bacterial infection and severe inflammation. In scalded skin model with MRSA infection, 8l not only effectively reduced bacterial load, but also decreased pro-inflammatory cytokines secretion and promoted collagen deposition to effectively reverse the progression of wound infection and inflammation by blocking cGAS/STING/NF-κB/IRF3 signaling pathway. In vitro model of RAW264.7 cells verified that 8l can inhibit MRSA-induced inflammation via regulating this pathway. All in all, dual anti-bacterial and anti-inflammatory agent 8l could heal MRSA-infected refractory scald by regulating cGAS/STING/NF-κB/IRF3 pathway.

MicroRNA let-7a regulation of Hantaan virus replication by Targeting FAS Signaling Pathways.

Hantaan virus (HTNV) infection in humans can cause hemorrhagic fever and renal syndrome (HFRS). Understanding host responses to HTNV infection is crucial for developing effective disease intervention strategies. Previous RNA-sequencing studies have investigated the role of microRNAs (miRNAs) in the post-transcriptional regulation of host genes in response to HTNV infection. In this study, we demonstrated that HTNV infection induces let-7a expression in human umbilical vein endothelial cells (HUVEC) and that HTNV G protein upregulates the expression of let-7a. miRNA let-7a mimics and inhibitors validated the predicted targets, including cell apoptosis genes (FAS, caspase-8, and caspase-3) and inflammatory factors (IL-6 and its related factors). Modulation of miRNA let-7a levels by miRNA mimics and inhibitors affected HTNV replication, indicating that HTNV modulates host miRNA expression to affect the outcome of the antiviral host response.

MCH-PAN: gastrointestinal polyp detection model integrating multi-scale feature information.

The rise of object detection models has brought new breakthroughs to the development of clinical decision support systems. However, in the field of gastrointestinal polyp detection, there are still challenges such as uncertainty in polyp identification and inadequate coping with polyp scale variations. To address these challenges, this paper proposes a novel gastrointestinal polyp object detection model. The model can automatically identify polyp regions in gastrointestinal images and accurately label them. In terms of design, the model integrates multi-channel information to enhance the ability and robustness of channel feature expression, thus better coping with the complexity of polyp structures. At the same time, a hierarchical structure is constructed in the model to enhance the model's adaptability to multi-scale targets, effectively addressing the problem of large-scale variations in polyps. Furthermore, a channel attention mechanism is designed in the model to improve the accuracy of target positioning and reduce uncertainty in diagnosis. By integrating these strategies, the proposed gastrointestinal polyp object detection model can achieve accurate polyp detection, providing clinicians with reliable and valuable references. Experimental results show that the model exhibits superior performance in gastrointestinal polyp detection, which helps improve the diagnostic level of digestive system diseases and provides useful references for related research fields.

High-performance bacterium-enhanced dual-compartment microbial fuel cells for simultaneous treatment of food waste oil and copper-containing wastewater.

Microbial fuel cells (MFCs) use the metabolic actions of microorganisms in an anode chamber to convert the chemical energy from wastewater into electrical energy. To improve the MFC power generation performance and chemical oxygen demand (COD) removal efficiency, Stenotrophomonas acidaminiphila was added to the anode chamber of a dual-compartment MFC. In this process, Stenotrophomonas acidaminiphila promotes the degradation of macromolecules such as bis(2-ethylhexyl) phthalate in food waste oil. Additionally, the generated electrical energy reduced Cu2+ in the copper-containing wastewater in the cathode chamber to Cu monomers. The maximum power density of the MFC was 49.5 ± 3.5 mW/m2, the maximum removal efficiencies of COD and Cu2+ were 63.5 ± 5.8% and 96.5 ± 1.0%, respectively, and Cu2+ was reduced to brick-red Cu monomers. This study provides insights into the simultaneous implementation of food waste oil treatment and metal resource recovery.

Structural biology of the human papillomavirus.

Human papillomavirus (HPV), known for its oncogenic properties, is the primary cause of cervical cancer and significantly contributes to mortality rates. It also plays a considerable role in the globally rising incidences of head and neck cancers. These cancers pose a substantial health burden worldwide. Current limitations in diagnostic and treatment strategies, along with inadequate coverage of preventive vaccines in low- and middle-income countries, hinder the progress toward the World Health Organization (WHO) HPV prevention and control targets set for 2030. In response to these challenges, extensive research in structural virology has explored the properties of HPV proteins, yielding crucial insights into the mechanisms of HPV infection that are important for the development of prevention and therapeutic strategies. This review highlights recent advances in understanding the structures of HPV proteins and discusses achievements and future opportunities for HPV vaccine development.

Progress in the study of the correlation between sepsis and intestinal microecology.

Sepsis, a disease with high incidence, mortality, and treatment costs, has a complex interaction with the gut microbiota. With advances in high-throughput sequencing technology, the relationship between sepsis and intestinal dysbiosis has become a new research focus. However, owing to the intricate interplay between critical illness and clinical interventions, it is challenging to establish a causal relationship between sepsis and intestinal microbiota imbalance. In this review, the correlation between intestinal microecology and sepsis was summarized, and new therapies for sepsis intervention based on microecological target therapy were proposed, and the shortcomings of bacterial selection and application timing in clinical practice were addressed. In conclusion, current studies on metabolomics, genomics and other aspects aimed at continuously discovering potential probiotics are all providing theoretical basis for restoring intestinal flora homeostasis for subsequent treatment of sepsis.

A feasibility study on utilizing machine learning technology to reduce the costs of gastric cancer screening in Taizhou, China.

Aim: To optimize gastric cancer screening score and reduce screening costs using machine learning models. Methods: This study included 228,634 patients from the Taizhou Gastric Cancer Screening Program. We used three machine learning models to optimize Li's gastric cancer screening score: Gradient Boosting Machine (GBM), Distributed Random Forest (DRF), and Deep Learning (DL). The performance of the binary classification models was evaluated using the area under the curve (AUC) and area under the precision-recall curve (AUCPR). Results: In the binary classification model used to distinguish low-risk and moderate- to high-risk patients, the AUC in the GBM, DRF, and DL full models were 0.9994, 0.9982, and 0.9974, respectively, and the AUCPR was 0.9982, 0.9949, and 0.9918, respectively. Excluding Helicobacter pylori IgG antibody, pepsinogen I, and pepsinogen II, the AUC in the GBM, DRF, and DL models were 0.9932, 0.9879, and 0.9900, respectively, and the AUCPR was 0.9835, 0.9716, and 0.9752, respectively. Remodel after removing variables IgG, PGI, PGII, and G-17, the AUC in GBM, DRF, and DL was 0.8524, 0.8482, 0.8477, and AUCPR was 0.6068, 0.6008, and 0.5890, respectively. When constructing a tri-classification model, we discovered that none of the three machine learning models could effectively distinguish between patients at intermediate and high risk for gastric cancer (F1 scores in the GBM model for the low, medium and high risk: 0.9750, 0.9193, 0.5334, respectively; F1 scores in the DRF model for low, medium, and high risks: 0.9888, 0.9479, 0.6694, respectively; F1 scores in the DL model for low, medium, and high risks: 0.9812, 0.9216, 0.6394, respectively). Conclusion: We concluded that gastric cancer screening indicators could be optimized when distinguishing low-risk and moderate to high-risk populations, and detecting gastrin-17 alone can achieve a good discriminative effect, thus saving huge expenditures.

A flexible 2.5D medical image segmentation approach with in-slice and cross-slice attention.

Deep learning has become the de facto method for medical image segmentation, with 3D segmentation models excelling in capturing complex 3D structures and 2D models offering high computational efficiency. However, segmenting 2.5D images, characterized by high in-plane resolution but lower through-plane resolution, presents significant challenges. While applying 2D models to individual slices of a 2.5D image is feasible, it fails to capture the spatial relationships between slices. On the other hand, 3D models face challenges such as resolution inconsistencies in 2.5D images, along with computational complexity and susceptibility to overfitting when trained with limited data. In this context, 2.5D models, which capture inter-slice correlations using only 2D neural networks, emerge as a promising solution due to their reduced computational demand and simplicity in implementation. In this paper, we introduce CSA-Net, a flexible 2.5D segmentation model capable of processing 2.5D images with an arbitrary number of slices. CSA-Net features an innovative Cross-Slice Attention (CSA) module that effectively captures 3D spatial information by learning long-range dependencies between the center slice (for segmentation) and its neighboring slices. Moreover, CSA-Net utilizes the self-attention mechanism to learn correlations among pixels within the center slice. We evaluated CSA-Net on three 2.5D segmentation tasks: (1) multi-class brain MR image segmentation, (2) binary prostate MR image segmentation, and (3) multi-class prostate MR image segmentation. CSA-Net outperformed leading 2D, 2.5D, and 3D segmentation methods across all three tasks, achieving average Dice coefficients and HD95 values of 0.897 and 1.40 mm for the brain dataset, 0.921 and 1.06 mm for the prostate dataset, and 0.659 and 2.70 mm for the ProstateX dataset, demonstrating its efficacy and superiority. Our code is publicly available at: https://github.com/mirthAI/CSA-Net.

Optimizing stability and motion in reverse shoulder arthroplasty with a 135° neck-shaft-angle: a computer model study of standard versus retentive humeral inserts.

Background: There has been a trend to shift from a 155° and 145° neck-shaft-angle (NSA) to a more "anatomical" reverse shoulder arthroplasty with less distalization and a 135° NSA. Multiple studies have shown that a 135° NSA is beneficial for motion. There are some concerns about primary implant stability with a 135° NSA. When instability is detected, increasing the tension with thicker inlays or changing the NSA to 145° are possible solutions. A retentive 135° (Ret135) inlay may be an alternative to avoiding increased distalization; however, retentive liners are widely regarded as salvage options reducing range of motion (ROM) and avoided by most surgeons. The hypothesis of this study was that a retentive 135° insert of the tested implant system may not have drawbacks for impingement-free ROM compared to a standard 145° insert (Sta145). Methods: In this computer model study, 22 computed tomographic scans (11 males/11 females) were used to create models with a constant humeral stem (Perform/Stryker) and +3 mm lateralized baseplate +36 mm glenosphere for females and +6 mm lateralized baseplate +39 mm glenosphere for males using Blueprint software (Imascap, Brest, France). A Ret135, standard 135° (Sta135), and Sta145 (+10°) insert were compared for adduction (ADD), extension (EXT), external rotation (ER), and internal rotation (IR) all with the arm at the side as well as for combined IR (CIR = EXT + IR) and combined notching relevant (CNR) ROM (EXT + ER + IR + ADD). Results: Sta135 showed significantly better ROM for ER, IR, ADD, EXT, CNR ROM, and CIR compared to Ret135 (P < .05) and significantly better EXT and ADD compared to Sta145 (P < .0001). Comparison of Ret135 and Sta145 showed equivalent ROM performance, which was slightly better but nonsignificant for ADD (P = .16), EXT (P = .31), CNR ROM (P = .7), and CIR (P = .54) in favor of Ret135. Isolated IR (P = .39) and ER (P = .32) were slightly better but nonsignificant in favor of a Sta145. Conclusion: For this implant system tested in a computer model, a 135° standard liner offers the best ROM. A 135° retentive liner maintains at least equivalent CIR and motion to prevent notching compared to a standard 145° liner. 135° retentive liners are more than salvage options and may help to prevent distalization and overtensioning by increased liner thickness.

Cholesterol suppresses AMFR-mediated PDL1 ubiquitination and degradation in HCC.

The degradation of proteasomes or lysosomes is emerging as a principal determinant of programmed death ligand 1 (PDL1) expression, which affects the efficacy of immunotherapy in various malignancies. Intracellular cholesterol plays a central role in maintaining the expression of membrane receptors; however, the specific effect of cholesterol on PDL1 expression in cancer cells remains poorly understood. Cholesterol starvation and stimulation were used to modulate the cellular cholesterol levels. Immunohistochemistry and western blotting were used to analyze the protein levels in the samples and cells. Quantitative real-time PCR, co-immunoprecipitation, and confocal co-localization assays were used for mechanistic investigation. A xenograft tumor model was constructed to verify these results in vivo. Our results showed that cholesterol suppressed the ubiquitination and degradation of PDL1 in hepatocellular carcinoma (HCC) cells. Further mechanistic studies revealed that the autocrine motility factor receptor (AMFR) is an E3 ligase that mediated the ubiquitination and degradation of PDL1, which was regulated by the cholesterol/p38 mitogenic activated protein kinase axis. Moreover, lowering cholesterol levels using statins improved the efficacy of programmed death 1 (PD1) inhibition in vivo. Our findings indicate that cholesterol serves as a signal to inhibit AMFR-mediated ubiquitination and degradation of PDL1 and suggest that lowering cholesterol by statins may be a promising combination strategy to improve the efficiency of PD1 inhibition in HCC.

Association between factors in life course and physiological disorders among the middle-aged and older population in Zhoushan city of Zhejiang province. / æµ™æ±ŸçœèˆŸå±±å¸‚ä¸­è€å¹´äººç¾¤ç”Ÿå‘½åŽ†ç¨‹å› ç´ ä¸Žç”Ÿç†å¤±è°ƒçš„å ³è”ç ”ç©¶.

OBJECTIVES: To analyze the associations between factors in life course and physiological disorders in the middle-aged and elderly population of Zhoushan city of Zhejiang province, and the mediating roles of lifestyle and mental health. METHODS: A total of 1553 island residents aged ≥45 years were enrolled from the Zhejiang Metabolic Syndrome Cohort Zhoushan Liuheng Sub-cohort. The demographic information, life-course information, lifestyle, and mental health information of participants were documented, and blood samples of were collected. The status of aging was evaluated by physiological disorders calculation model developed by authors previously. The Shapley value decomposition method was used to assess the cumulative and relative contribution of multiple factors in life course to the aging. Principal component analysis and hierarchical cluster analysis were used to classify subgroups. General linear regression model was used to assess the associations between the life-course subgroups and physiological disorders. Five key factors associated with aging were finally identified. Logistic regression model, general linear regression model, and mediation analysis model were used to assess the complex associations between life-course subgroups, key factors, unhealthy lifestyle, mental health, and aging. RESULTS: Shapley value decomposition method indicated that eight types of life-course factors explained 6.63% (SE=0.0008) of the individual physiological disorders variance, with the greatest relative contribution (2.78%) from adversity experiences in adulthood. The study participants were clustered into 4 subgroups, and subgroups experiencing more adversity in adulthood and having low educational attainment or experiencing more trauma and having poorer relationships in childhood had significantly higher levels of physiological disorders. Life-course subgroups and key factors (childhood trauma and health, adversity experience in adulthood, and lower education) were positively associated with unhealthy lifestyles (ß=0.12-0.41, P<0.05). In addition, life-course subgroups and key factors (adversity experience in adulthood) were positively associated with psychological problems (OR=2.14-4.68, P<0.05). Unhealthy lifestyle scores showed a marginal significant association with physiological disorders (ß=0.03, P=0.055). However, no significant association was found between psychological problems and physiological disorders (ß=0.03, P=0.748). The results of the mediation analysis model suggested that unhealthy lifestyles partially mediated the associations between life-course subgroups, adversity experience in adulthood and physiological disorders. CONCLUSIONS: Multiple life-course factors contribute about 6% of the variance in physiological disorders in the middle aged and elderly population of the study area; subgroups with adverse life course experiences have higher levels of aging; and the association may be partially mediated by unhealthy lifestyles.

Decimeter-depth and polarization addressable color 3D meta-holography.

Fueled by the rapid advancement of nanofabrication, metasurface has provided unprecedented opportunities for 3D holography. Large depth 3D meta-holography not only greatly increases information storage capacity, but also enables distinguishing of the relative spatial relationship of 3D objects, which has important applications in fields like optical information storage and medical diagnosis. Although the methods based on Fresnel diffraction theory can reconstruct the real depth information of 3D objects, the maximum depth is only 2 mm. Here, we develop a 3D meta-holography based on angular spectrum diffraction theory to break through the depth limit. By developing the angular spectrum diffraction theory into meta-holography, the metasurface structure with independent polarization control is used to create a polarization multiplexing 3D meta-hologram. The fabricated amorphous silicon metasurface increases the depth range by 47.5 times and realizes 0.95 dm depth reconstruction for polarization independent and different color 3D meta-hologram in visible. Such polarization controlled large-depth color meta-holography is expected to open avenue for data storage, display, information security and virtual reality.

Causal relationships of infection with Helicobacter pylori and herpesvirus on periodontitis: A Mendelian randomization study.

Background: To explore the causal association between Helicobacter pylori (H. pylori) infection, herpesvirus infection and periodontitis (PD) from a genetic perspective using Mendelian randomization (MR). Methods: The PD data were derived from genome-wide association study (GWAS) from the Dental Endpoints (GLIDE) consortium, and the FinnGen Biobank provided data on H. pylori and herpesvirus infections. In addition, we examined GWAS data for subtypes of H. pylori and herpesvirus infection. Inverse variance weighting (IVW) was selected as a major analysis technique, and weighted median (WM), weighted model, simple model, and MR-Egger regression were added as supplementary methods. To verify the findings, the effects of pleiotropy and heterogeneity were assessed. Results: Genetically predicted H. pylori infection (OR = 0.914, 95%CI = 0.693-1.205, P = 0.523), anti-H. pylori VacA (OR = 0.973, 95%CI = 0.895-1.057, P = 0.515), anti-H. pylori CagA (OR = 1.072, 95%CI = 0.986-1.164; P = 0.102), Epstein-Barr virus (EBV) infection (OR = 1.026, 95%CI = 0.940-1.120, P = 0.567), Herpes simplex virus (HSV) infection (OR = 0.962, 95%CI = 0.883-1.048, P = 0.372), cytomegalovirus (CMV) infection (OR = 1.025, 95%CI = 0.967-1.088, P = 0.415), EBV nuclear antigen-1 (EBNA1) (OR = 1.061, 95%CI = 0.930-1.209, P = 0.378), EBV virus capsid antigen (VCA) (OR = 1.043, 95CI% = 0.890-1.222, P = 0.603), HSV-1 (OR = 1.251, 95%CI = 0.782-2.001, P = 0.351), HSV-2 (OR = 1.020, 95%CI = 0.950-1.096, P = 0.585), CMV IgG (OR = 0.990, 95CI% = 0.882-1.111, P = 0.861) were not associated with PD, indicated that H. pylori and herpesvirus infection had no causal relationship to PD. Reverse studies also found no cause effect of PD on H. pylori or herpesvirus infection. The results of the sensitivity analysis suggested the robustness of the MR results. Conclusion: This study offered preliminary proof that H. pylori and herpesvirus infections were not causally linked to PD, and vice versa. However, more robust instrumental variables (IVs) and larger samples of GWAS data were necessary for further MR analysis.

Research on Reverse Osmosis (RO)/Nanofiltration (NF) Membranes Based on Thin Film Composite (TFC) Structures: Mechanism, Recent Progress and Application.

The global shortage of clean water is a major problem, even in water-rich regions. To solve this problem, low-cost and energy-efficient water treatment methods are needed. Membrane separation technology (MST), as a separation method with low energy consumption, low cost, and good separation effect, has been widely used to deal with seawater desalination, resource recovery, industrial wastewater treatment, and other fields. With the continuous progress of scientific and technological innovation and the increasing demand for use, NF/RO membranes based on the TFC structure are constantly being upgraded. This paper presents the recent research progress of NF and RO membranes based on TFC structures and their applications in different fields, especially the formation mechanism and regulation of selective layer structures and the modification methods of selective layers. Our summary provides fundamental insights into the understanding of NF and RO membrane processes and hopefully triggers further thinking on the development of membrane filtration process optimization.

Controllable Design of Polyamide Composite Membrane Separation Layer Structures via Metal-Organic Frameworks: A Review.

Optimizing the structure of the polyamide (PA) layer to improve the separation performance of PA thin-film composite (TFC) membranes has always been a hot topic in the field of membrane preparation. As novel crystalline materials with high porosity, multi-functional groups, and good compatibility with membrane substrate, metal-organic frameworks (MOFs) have been introduced in the past decade for the modification of the PA structure in order to break through the separation trade-off between permeability and selectivity. This review begins by summarizing the recent progress in the control of MOF-based thin-film nanocomposite (TFN) membrane structures. The review also covers different strategies used for preparing TFN membranes. Additionally, it discusses the mechanisms behind how these strategies regulate the structure and properties of PA. Finally, the design of a competent MOF material that is suitable to reach the requirements for the fabrication of TFN membranes is also discussed. The aim of this paper is to provide key insights into the precise control of TFN-PA structures based on MOFs.

GAMG ameliorates silica-induced pulmonary inflammation and fibrosis via the regulation of EMT and NLRP3/TGF-ß1/Smad signaling pathway.

Silicosis is an occupational disease caused by exposure to silica characterized by pulmonary inflammation and fibrosis, for which there is a lack of effective drugs. Glycyrrhetinic acid 3-O-ß-D-glucuronide (GAMG) can treat silicosis due to its anti-inflammatory and anti-fibrotic properties. Here, the effect of therapeutic interventions of GAMG was evaluated in early-stage and advanced silicosis mouse models. GAMG significantly improved fibrotic pathological changes and collagen deposition in the lungs, alleviated lung inflammation in the BALF, reduced the expression of TNF-α, IL-6, NLRP3, TGF-ß1, vimentin, Col-Ⅰ, N-cadherin, and inhibited epithelial-mesenchymal transition (EMT), thereby ameliorating pulmonary fibrosis. Moreover, the dose of 100 mg/kg GAMG can effectively prevent early-stage silicosis, while that of 200 mg/kg was recommended for advanced silicosis. In vitro and in vivo study verified that GAMG can suppress EMT through the NLRP3/TGF-ß1/Smad2/3 signaling pathway. Therefore, GAMG could be a promising preventive (early-stage silicosis) and therapeutic (advanced silicosis) strategy, which provides a new idea for formulating prevention and treatment strategies.

An fusaric acid-based CRISPR library screen identifies MDH2 as a broad-spectrum regulator of Fusarium toxin-induced cell death.

Fusarium mycotoxins are of great concern because they are the most common food-borne mycotoxins and environmental contaminants worldwide. Fusaric acid (FA), Deoxynivalenol (DON), Zearalenone (ZEA), T-2 toxin (T-2), and Fumonisin B1 (FB1) are important Fusarium toxins contaminating feeds and food and can cause serious health problems. FA can synergize with some other Fusarium toxins to enhance overall toxicity. However, the underlying molecular mechanism remains poorly understood. In this study, our CRISPR screening revealed Malate dehydrogenase 2 (MDH2) and Pyruvate dehydrogenase E1 subunit beta (PDHB) are the key genes for FA-induced cell death. Pathways associated with mitochondrial function, notably the TCA cycle, play a significant role in FA cytotoxicity. We found that MDH2 and PDHB depletion reduced FA-induced cell death, ROS accumulation, and the expression of caspase-3 and HIF-1α. The cell viability assays and flow cytometry demonstrated that MDH2 knockout but not PDHB decreased DON, ZEA, T-2, and FB1-induced cytotoxicity, apoptosis, and ROS accumulation. MDH2 inhibitor LW6 also decreased DON, ZEA, T-2, and FB1-induced toxicity. This suggested that MDH2, but not PDHB, is a common regulator of broad-spectrum Fusarium toxin (FA, DON, ZEA, T-2, and FB1)-induced cell death. Our work provides new avenues for the treatment of Fusarium toxin toxicity.

Polypyrrole/iron-glycol chitosan nanozymes mediate M1 macrophages to enhance the X-ray-triggered photodynamic therapy for bladder cancer by promoting antitumor immunity.

X-ray Photodynamic Therapy (XPDT) is an emerging, deeply penetrating, and non-invasive tumor treatment that stimulates robust antitumor immune responses. However, its efficacy is often limited by low therapeutic delivery and immunosuppressant within the tumor microenvironment. This challenge can potentially be addressed by utilizing X-ray responsive iron-glycol chitosan-polypyrrole nanozymes (GCS-I-PPy NZs), which activate M1 macrophages. These nanozymes increase tumor infiltration and enhance the macrophages' intrinsic immune response and their ability to stimulate adaptive immunity. Authors have designed biocompatible, photosensitizer-containing GCS-I-PPy NZs using oxidation/reduction reactions. These nanozymes were internalized by M1 macrophages to form RAW-GCS-I-PPy NZs. Authors' results demonstrated that these engineered macrophages effectively delivered the nanozymes with potentially high tumor accumulation. Within the tumor microenvironment, the accumulated GCS-I-PPy NZs underwent X-ray irradiation, generating reactive oxygen species (ROS). This ROS augmentation significantly enhanced the therapeutic effect of XPDT and synergistically promoted T cell infiltration into the tumor. These findings suggest that nano-engineered M1 macrophages can effectively boost the immune effects of XPDT, providing a promising strategy for enhancing cancer immunotherapy. The ability of GCS-I-PPy NZs to mediate M1 macrophage activation and increase tumor infiltration highlights their potential in overcoming the limitations of current XPDT approaches and improving therapeutic outcomes in melanoma and other cancers.

A pH-responsive novel delivery system utilizing carbon quantum dots loaded with PT2385 for targeted inhibition of HIF-2α in the treatment of osteoarthritis.

BACKGROUND: Osteoarthritis (OA) is a progressive joint disorder marked by the degradation of cartilage. Elevated concentrations of hypoxia-inducible factor-2α (HIF-2α) are intricately linked to the pathological development of OA. PT2385 has demonstrated effective inhibition of HIF-2α, thereby potentially impeding the initial advancement of OA. Nevertheless, challenges persist, including limited penetration into the deeper layers of cartilage, issues related to charge rejection, and a heightened rate of clearance from the joint. These constraints necessitate further consideration and exploration. METHODS: It has been demonstrated that PT2385 exhibits efficient inhibition of HIF-2α expression, thereby contributing to the delay in the progression of osteoarthritis. The pH-responsive attributes of carbon quantum dots, specifically those employing m-phenylenediamine (m-CQDs) coated with bovine serum albumin (BSA), have been systematically evaluated. In both in vitro settings involving cartilage explants and in vivo experiments, the efficacy of BSA-m-CQDs-PT2385 (BCP) has been confirmed in facilitating the transport of PT2385 to the middle and deep layers of cartilage. Furthermore, the BCP system demonstrates controlled drug release contingent upon alterations in environmental pH. RESULTS: While the use of PT2385 alone provides protective effects on chondrocytes within an inflamed environment, there exists an opportunity for further enhancement in its efficacy when administered via intra-articular injection. The BCP formulation, characterized by appropriate particle size and charge, facilitates seamless penetration into cartilage tissue. Additionally, BCP demonstrates the capability to release drugs in response to changes in environmental pH. In vitro experiments reveal that BCP effectively inhibits Hif-2α expression and catabolic factors in chondrocytes. Notably, cartilage explants and in vivo experiments indicate that BCP surpasses PT2385 alone in inhibiting the expression of HIF-2α and matrix metalloproteinase 13, particularly in the middle and deep layers. CONCLUSIONS: The BCP drug delivery system exhibits selective release of PT2385 in response to pH changes occurring during the progression of osteoarthritis (OA), thereby inhibiting HIF-2α expression deep within the cartilage. The use of BCP significantly augments the capacity of PT2385 to retard both cartilage degeneration and the progression of osteoarthritis. Consequently, BCP as an innovative approach utilizing m-CQDs to deliver PT2385 into articular cartilage, shows potential for treating osteoarthritis.This strategy opens new avenues for osteoarthritis treatment.