Identification and Construction of a Disulfidptosis-Mediated Diagnostic Model and Associated Immune Microenvironment of Osteoarthritis from the Perspective of PPPM.

Background: Osteoarthritis (OA) is a major cause of human disability. Despite receiving treatment, patients with the middle and late stage of OA have poor survival outcomes. Therefore, within the framework of predictive, preventive, and personalized medicine (PPPM/3PM), early personalized diagnosis of OA is particularly prominent. PPPM aims to accurately identify disease by integrating multiple omic techniques; however, the efficiency of currently available methods and biomarkers in predicting and diagnosing OA should be improved. Disulfidptosis, a novel programmed cell death mechanism and appeared in particular metabolic status, plays a mysterious characteristic in the occurrence and development of OA, which warrants further investigation. Methods: In this study, we integrated three public datasets from the Gene Expression Omnibus (GEO) database, including 26 OA samples and 20 normal samples. Via a series of bioinformatic analysis and machine learning, we identified the diagnostic biomarkers and several subtypes of OA. Moreover, the expression of these biomarkers were verified in our in-house cohort and the single cell dataset. Results: Three significant regulators of disulfidptosis (NCKAP1, OXSM, and SLC3A2) were identified through differential expression analysis and machine learning. And a nomogram constructed based on these three regulators exhibited ideal efficiency in predicting early- and late-stage OA. Furthermore, based on the expression of three regulators, we identified two disulfidptosis-related subtypes of OA with different infiltration of immune cells and personalized expression level of immune checkpoints. Notably, the expression of the three regulators was demonstrated in a single-cell RNA profile and verified in the synovial tissue in our in-house cohort including 6 OA patients and 6 normal people. Finally, an efficient disulfidptosis-mediated diagnostic model was constructed for OA, with the AUC value of 97.6923% in the training set and 93.3333% and 100% in two validation sets. Conclusion: Overall, with regard to PPPM, this study provided novel insights into the role of disulfidptosis regulators in the personalized diagnosis and treatment of OA.

The role of programmed cell death in osteosarcoma: From pathogenesis to therapy.

Osteosarcoma (OS) is a prevalent bone solid malignancy that primarily affects adolescents, particularly boys aged 14-19. This aggressive form of cancer often leads to deadly lung cancer due to its high migration ability. Experimental evidence suggests that programmed cell death (PCD) plays a crucial role in the development of osteosarcoma. Various forms of PCD, including apoptosis, ferroptosis, autophagy, necroptosis, and pyroptosis, contribute significantly to the progression of osteosarcoma. Additionally, different signaling pathways such as STAT3/c-Myc signal pathway, JNK signl pathway, PI3k/AKT/mTOR signal pathway, WNT/ß-catenin signal pathway, and RhoA signal pathway can influence the development of osteosarcoma by regulating PCD in osteosarcoma cell. Therefore, targeting PCD and the associated signaling pathways could offer a promising therapeutic approach for treating osteosarcoma.

Exploring a specialized programmed-cell death patterns to predict the prognosis and sensitivity of immunotherapy in cutaneous melanoma via machine learning.

The mortality and therapeutic failure in cutaneous melanoma (CM) are mainly caused by wide metastasis and chemotherapy resistance. Meanwhile, immunotherapy is considered a crucial therapy strategy for CM patients. However, the efficiency of currently available methods and biomarkers in predicting the response of immunotherapy and prognosis of CM is limited. Programmed cell death (PCD) plays a significant role in the occurrence, development, and therapy of various malignant tumors. In this research, we integrated fourteen types of PCD, multi-omics data from TCGA-SKCM and other cohorts in GEO, and clinical CM patients to develop our analysis. Based on significant PCD patterns, two PCD-related CM clusters with different prognosis, tumor microenvironment (TME), and response to immunotherapy were identified. Subsequently, seven PCD-related features, especially CD28, CYP1B1, JAK3, LAMP3, SFN, STAT4, and TRAF1, were utilized to establish the prognostic signature, namely cell death index (CDI). CDI accurately predicted the response to immunotherapy in both CM and other cancers. A nomogram with potential superior predictive ability was constructed, and potential drugs targeting CM patients with specific CDI have also been identified. Given all the above, a novel CDI gene signature was indicated to predict the prognosis and exploit precision therapeutic strategies of CM patients, providing unique opportunities for clinical intelligence and new management methods for the therapy of CM.

What are exposure biomarkers of rare earth elements for the ionic rare earth occupational population?

Rare earth elements (REEs) are widely utilized in industries. However, The specific exposure features of REEs and potential biomarkers of exposure in occupational populations remain unclear. In this study, we evaluated the external and internal REEs exposure levels among the participants working in the ionic rare earth smelting plant. For the external exposure, the concentrations of 14 REEs and total rare earth elements (ΣREEs) in airborne particles were significantly elevated in the REEs-exposed versus non-exposed group (P < 0.05). Meanwhile, the levels of Yttrium (Y), Gadolinium (Gd), Terbium (Tb), Dysprosium (Dy), Holmium (Ho), Thulium (Tm), Ytterbium (Yb), and ΣREEs in urine were higher in the REEs-exposed group compared to the non-exposed group (P < 0.05). Notably, a significant positive correlation was observed between Y in both the airborne particles and urine samples as well as Gd, and the Spearman correlation coefficient was 0.53 and 0.39 respectively, both P < 0.05. Conversely, no statistically significant differences were found in the levels of 15 REEs or ΣREEs in the blood samples between the REEs-exposed group and non-exposed group. Moreover, the concentrations of ΣREEs and 9 REEs in nail samples of the exposed group were significantly higher than those of the non-exposed group (P < 0.05), and the composition ratios of REEs in the nail samples closely resembled those found in individual airborne particles. Therefore, nail and urine samples were proposed to reflect long-term and short-term exposure to ionic rare earth respectively. Exposure biomarkers confirmed by external and internal exposure characteristics accurately provide the situation of human exposure to REEs environment, and have profound significance for monitoring and evaluating the level of REEs pollution in human body. It also provides a vital basis to find out the effect biomarkers, susceptible biomarkers and the health effects of rare earth environment for the future research.

Role of lipid metabolism gene KLF4 in osteoarthritis.

INTRODUCTION: Osteoarthritis (OA) is a common degenerative disease of joints, which can appear in almost any joint of the body. Therefore, the widespread occurrence of this disease has a huge impact on the lives of patients around the world. As an important part of metabolism, lipid metabolism is closely related to the occurrence and development of osteoarthritis. METHOD: We screened UGCG and KLF4 based on weighted co-expression network analysis (WGCNA) and SVM-REF analysis. The data from Gene Expression Omnibus (GEO) and single-cell data verified the expression of these two genes. We analyzed KLF4-related genes and established a diagnosis model of OA related to lipid metabolism through the least absolute shrinkage and selection operator (LASSO) analysis. RT-PCR was used to verify the expression of KLF4 in osteoarthritis. RESULTS: Ten important lipid metabolism related genes (LMRGs) in OA were obtained. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that they are involve in the formation of immune microenvironment in osteoarthritis. CIBERSORT analysis revealed that there were significant differences in the immune microenvironment between osteoarthritis patients and normal controls. RT-PCR results showed that the expression of KLF4 in OA samples was lower than that in normal samples. The diagnostic model can be used to diagnose OA patients well. CONCLUSIONS: Overall, we demonstrated the potential relationship between the abnormal lipid metabolism and the pathological process of OA. Finally, we identified KLF4 as our significant LMRG and constructed a KLF4-related scoring model to accurately diagnose OA. In conclusion, therapy strategies targeting on regulating lipid metabolism may become a key factor in treating OA. Key Points (a) We identified the significant LMRG KLF4 and constructed a novel KLF4-related scoring model for the accuracy diagnosis of OA. (b) The potential relationship between lipid metabolism and the immune microenvironment in OA was demonstrated in our research. (c) The relationship of lipid metabolism and OA has been further improved in our research and provided novel insight for the diagnosis and therapy for OA patients.

Identification of necroptosis-related features in diabetic nephropathy and analysis of their immune microenvironent and inflammatory response.

Background: Diabetic nephropathy (DN) was considered a severe microvascular complication of diabetes, which was recognized as the second leading cause of end-stage renal diseases. Therefore, identifying several effective biomarkers and models to diagnosis and subtype DN is imminent. Necroptosis, a distinct form of programmed cell death, has been established to play a critical role in various inflammatory diseases. Herein, we described the novel landscape of necroptosis in DN and exploit a powerful necroptosis-mediated model for the diagnosis of DN. Methods: We obtained three datasets (GSE96804, GSE30122, and GSE30528) from the Gene Expression Omnibus (GEO) database and necroptosis-related genes (NRGs) from the GeneCards website. Via differential expression analysis and machine learning, significant NRGs were identified. And different necroptosis-related DN subtypes were divided using consensus cluster analysis. The principal component analysis (PCA) algorithm was utilized to calculate the necroptosis score. Finally, the logistic multivariate analysis were performed to construct the necroptosis-mediated diagnostic model for DN. Results: According to several public transcriptomic datasets in GEO, we obtained eight significant necroptosis-related regulators in the occurrence and progress of DN, including CFLAR, FMR1, GSDMD, IKBKB, MAP3K7, NFKBIA, PTGES3, and SFTPA1 via diversified machine learning methods. Subsequently, employing consensus cluster analysis and PCA algorithm, the DN samples in our training set were stratified into two diverse necroptosis-related subtypes based on our eight regulators' expression levels. These subtypes exhibited varying necroptosis scores. Then, we used various functional enrichment analysis and immune infiltration analysis to explore the biological background, immune landscape and inflammatory status of the above subtypes. Finally, a necroptosis-mediated diagnostic model was exploited based on the two subtypes and validated in several external verification datasets. Moreover, the expression level of our eight regulators were verified in the singe-cell level and glomerulus samples. And we further explored the relationship between the expression of eight regulators and the kidney function of DN. Conclusion: In summary, our necroptosis scoring model and necroptosis-mediated diagnostic model fill in the blank of the relationship between necroptosis and DN in the field of bioinformatics, which may provide novel diagnostic insights and therapy strategies for DN.

The role of exosomes and their enhancement strategies in the treatment of osteoarthritis.

With the increasingly prominent problem of population aging, osteoarthritis (OA), which is closely related to aging, has become a serious illness affecting the lives and health of elderly individuals. However, effective treatments are still lacking. OA is typically considered a low-grade inflammatory state. The inflammatory infiltration of macrophages, neutrophils, T cells, and other cells is common in diseased joints. These cells create the inflammatory environment of OA and are involved in the onset and progression of the disease. Exosomes, a type of complex vesicle containing abundant RNA molecules and proteins, play a crucial role in the physiological and pathological processes of an organism. In comparison to other therapeutic methods such as stem cells, exosomes have distinct advantages of precise targeting and low immunogenicity. Moreover, research and techniques related to exosomes are more mature, indicating a promising future in disease treatment. Many studies have shown that the impact of exosomes on the inflammatory microenvironment directly or indirectly leads to the occurrence of various diseases. Furthermore, exosomes can be helpful in the management of illnesses. This article provides a comprehensive review and update on the research of exosomes, a type of extracellular vesicle, in the treatment of OA by modulating the inflammatory microenvironment. It also combines innovative studies on the modification of exosomes. In general, the application of exosomes in the treatment of OA has been validated, and the introduction of modified exosome technology holds potential for enhancing its therapeutic efficacy.

Lanthanide-doped upconversion glass-ceramic photocatalyst fabricated from fluorine-containing waste for the degradation of organic pollutants.

Fluorine-containing waste is one kind of hazardous waste characteristic by hard disposal and utilization, it is an attractive way to prepare for fluoride-based luminescent matrix. In this work, to realize the high value-added utilization of fluorine-containing waste and reduce cost of the raw materials for preparation near-infrared (NIR) glass-ceramic (GC) photocatalyst, the pure fluoride of luminescent matrix was replaced by introducing fluorine-containing waste. The waste contained NIR GC photocatalyst was synthesis by the method of facile in-situ etching of an upconversion GC with HCl, which possesses core-shell structure, where the GC micro-powder including optically active centers lanthanides doped CaF2 nanocrystals are displayed as the core, and the BiOCl is as the superficial coating. The upconversion emission performance of CaF2 based luminescent matrix in photocatalyst is not weakened with HCl etching. NIR GC photocatalyst has high methyl orange and enrofloxacin degradation rate of 86 % and 82 % over 180 min after NIR light irradiation, respectively. The UV-Vis-NIR photocatalytic activity was enhanced degradation rate (93 % in 15 min) of enrofloxacin compared with those of commercial P25 and BiOCl. In addition, the photocatalyst had stable photocatalytic activity and it also can be regenerated. The study provided references for high value-added utilization fluorine-containing waste.

Blue Emission of Tetrafluorobenzocarbazole Under the Interactions of Nitrogen-oxygen Saturated hydrogen Bonds with Aggregated Proton Acid.

Two novel tetrafluorobenzocarbazole and containing the amino branch introduced at the end of the molecule are synthesized by a simple method. The tetrafluorobenzocarbazole as the electron donor with electron-rich fluoride ions connected by π-benzyl ring conjugation structure, which affects the overall electron cloud density. Moreover, the amino branch introduced at the end of the molecule, which makes it easy to form intermolecular hydrogen bonds and affected photophysical properties. Meanwhile, the photophysical property of both compounds are discussed under different acidic conditions. The UV-absorption show that around ~286 nm is mainly attributed to the strong structural absorption band peak of the π-π ∗ transition of the carbazole moiety, and the irregular absorption band around ~314 nm and ~326 nm are mainly attributed to the n-π ∗ transition of the carbazole group conjugate with the adjacent molecule. The emission spectrum of both compounds showed that the intensity of fluorescence decreased in different degrees after the addition of the acidic solution. Furthermore, the electrochemical properties were evidenced by cyclic voltammetry (CV) and density functional theory (DFT) calculations, and the orbital conformation (HOMOs-LUMOs) was simulated by Gaussian 09 software and its crystal structure was observed by X-ray diffraction (XRD). The results exhibited that both compounds are electrochemically stable blue small-molecule fluorescent substances, and expected that both compounds can be novel and stable acid-sensitive organic blue-light materials.

Mechanism and Role of Endoplasmic Reticulum Stress in Osteosarcoma.

Osteosarcoma is the most common malignant bone tumor, often occurring in children and adolescents. The etiology of most patients is unclear, and the current conventional treatment methods are chemotherapy, radiotherapy, and surgical resection. However, the sensitivity of osteosarcoma to radiotherapy and chemotherapy is low, and the prognosis is poor. The development of new and useful treatment strategies for improving patient survival is an urgent need. It has been found that endoplasmic reticulum (ER) stress (ERS) affects tumor angiogenesis, invasion, etc. By summarizing the literature related to osteosarcoma and ERS, we found that the unfolded protein response (UPR) pathway activated by ERS has a regulatory role in osteosarcoma proliferation, apoptosis, and chemoresistance. In osteosarcoma, the UPR pathway plays an important role by crosstalk with autophagy, oxidative stress, and other pathways. Overall, this article focuses on the relationship between ERS and osteosarcoma and reviews the potential of drugs or gene targets associated with ERS for the treatment of osteosarcoma.

Efficient Near-Infrared Response Antibacterial Ceramics Based on the Method of Facile In Situ Etching Upconversion Glass-Ceramics.

As the world is faced with the coronavirus disease 2019 (COVID-19) pandemic, photocatalytic antibacterial ceramics can reduce the consumption of disinfectants and improve the safety of the public health environment. However, these antibacterial ceramics are often limited by poor stability and low light utilization efficiency. Herein, an antibacterial ceramic was developed via the method of facile in situ etching of upconversion glass-ceramics (UGC) (FIEG) with HCl, in which the BiOCl nanosheets were in situ grown on the surface of GC to improve its stability and antibacterial activity. The results suggest that the upconversion antibacterial ceramics can harvest and utilize near-infrared (NIR) photons efficiently, which display notable antibacterial activity for Escherichia coli (E. coli) under NIR (≥780 nm) and visible light (420-780 nm) irradiation, with a maximum inactivation rate of 7.5 log in 30 min. Meanwhile, in the cycle experiment, more than 6 log inactivation of E. coli was achieved using an antibacterial ceramic sheet after 2-h NIR light irradiation, and the stability of the antibacterial ceramic was discussed. Furthermore, the reactive species, fluorescence-based live/dead cells, and cell structure of bacteria were analyzed to verify the antibacterial mechanism. This study provides a promising strategy for the construction of efficient and stable antibacterial ceramics.

Osteosarcoma subtypes based on platelet-related genes and tumor microenvironment characteristics.

Background: Osteosarcoma is a common metastatic tumor in children and adolescents. Because of its easy metastasis, patients often show a poor prognosis. Recently, researchers have found that platelets are closely related to metastasis of a variety of malignant tumors, but the role of platelets related characteristics in osteosarcoma is still unknown. The purpose of this study is to explore the characteristics of platelet-related subtypes and cell infiltration in tumor microenvironment. Methods: We collected osteosarcoma cohorts from TCGA and GEO databases, and explored the molecular subtypes mediated by platelet-related genes and the related TME cell infiltration according to the expression of platelet-related genes in osteosarcoma. In addition, we also explored the differentially expressed genes (DEGs) among different molecular subtypes and established a protein-protein interaction network (PPI). Then we constructed a platelet scoring model by Univariate cox regression and least absolute shrinkage and selection operator (Lasso) cox regression model to quantify the characteristics of platelet in a single tumor. RT-PCR was used to investigate the expression of six candidate genes in osteosarcoma cell lines and normal osteoblast lines. Finally, we also predicted potential drugs with therapeutic effects on platelet-related subtypes. Results: We found that platelet-related genes (PRGs) can distinguish osteosarcoma into two different platelet-related subtypes, C1 and C2. And the prognosis of the C2 subtype was significantly worse than that of C1 subtype. The results of ESTIMATE analysis and GO/KEGG enrichment showed that the differences between different subtypes were mainly concentrated in immune response pathways, and the immune response of C2 was inhibited relative to C1. We further studied the relationship between platelet-related subtypes and immune cell infiltration. We found that the distribution of most immune cells in C1 subtype was higher than that in C2 subtype, and there was a correlation between C1 subtype and more immune cells. Finally, we screened the PRGs related to the prognosis of osteosarcoma through Univariate Cox regression, established independent prognostic platelet characteristics consisting of six genes to predict the prognosis of patients with OS, and predicted the drugs that may be used in the treatment of osteosarcoma. RT-PCR was used to verify the expression of candidate genes in osteosarcoma cells. Conclusion: Platelet scoring model is a significant biomarker, which is of great significance to determine the prognosis, molecular subtypes, characteristics of TME cell infiltration and therapy in patients with OS.

Bioactivity and Cell Imaging of Antitumor Fluorescent Agents (Curcumin Derivatives) Coated by Two-Way Embedded Cyclodextrin Strategy.

Curcumin has a wide range of pharmacological activities, which can be used to treat tumors, inflammation and other diseases. However, curcumin's poor solubility and low bioavailability limit its application. In this article, the structure of curcumin was modified with boron trifluoride ether to change fluorescent labeling. The compounds were then embedded into the hydrophobic cavity of α-cyclodextrin and hydroxypropyl ß-cyclodextrin to form inclusion complexes. The two inclusion complexes have excellent photophysical properties, and the maximum emission wavelength is in the range of 550-565 nm. In addition, the two compounds were applied to the fluorescence imaging of HCT-116 cells and HeLa cells, and the proliferation toxicity of the compounds was detected. Both compounds showed certain inhibitory effects on the proliferation of cancer cells. In short, the fluorescent drug molecule synthesized in this article has great reference value for the development of new dosage forms of curcumin.

A multiple acetal chalcone-BODIPY-based fluorescence: synthesis, physical property, and biological studies.

Fluorescent probes with outstanding physical and biological properties are superior for functional fluorescent dyes design. However, few studies pay attention to the stability of specific groups in fluorescent probes. The aldehyde group in the fluorescent probe is highly active but unstable under certain conditions. Therefore, we introduced ethoxy groups to realize the conversion to aldehyde groups under acidic conditions and avoid the instability of straightforward aldehyde groups. In this work, two fluorophores based on the multi acetal difluoroboraindacene (BODIPY) units with combination of the pharmaceutical intermediate chalcone have been firstly developed. In the design part, chalcone was introduced as a medium for fluorophore and multiple acetal. The mild synthesis strategy is based on the ligand ((Z)-2-chloro-1-(difluoroboranyl)-5-((4-ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene)(phenyl)methyl)-1H-pyrrole) and connects with chalcone in (2E,2'E)-3,3'-(1,3-phenylene)bis(1-(2,4-bis(2,2-diethoxyethoxy)phenyl)prop-2-en-1-one). The emission wavelengths of the products are around 530 nm with high fluorescence intensity. To highlight the biological characteristics of these novel BODIPY fluorescents, we further demonstrated biological analysis studies on MTT and flow cytometry assays. The IC50 values of BODIPY 5 ranged from 79 ± 6.11 to 63 ± 5.67 µM and BODIPY 6 were found to be 86 ± 4.07 to 58 ± 10.51 µM in tested cell lines. Flow cytometry data analysis shows that the representative agent 6 and reference have similar rational apoptosis rates in first quadrant. Last but not least, 6 shows outstanding biological compatibility and cell imaging potential in live cell imaging and in vivo assay, not only is the fluorescence prominent enough, but also rapidly distributes. Thus, our study reports a mild synthesis strategy and full biological analysis on BODIPY fluorescents, and the subtle modulation of the physical and biological properties by pharmaceutical substituents makes these designed chalcone-BODIPY-based dyes hopeful to realize drug functional fluorescent dyes. Two new highly sensitive BODIPY fluorophores are synthesized based on the ligand ((Z)-2-chloro-1-(difluoroboranyl)-5-((4-ethyl-3,5-dimethyl-2H-pyrrol-2-ylidene)(phenyl)methyl)-1H-pyrrole), which connects with chalcone in (2E,2'E)-3,3'-(1,3/4-phenylene)bis(1-(2,4-bis(2,2-diethoxyethoxy)phenyl)prop-2-en-1-one). Multiple acetals were introduced and the physical and biological properties of BODIPYs are described with MTT assay and in vitro and in vivo imaging.