PS-MPs promotes the progression of inflammation and fibrosis in diabetic nephropathy through NLRP3/Caspase-1 and TGF-ß1/Smad2/3 signaling pathways.

BACKGROUND: Diabetic nephropathy (DN) is a prevalent chronic microvascular complication of diabetes and the leading cause of end-stage renal disease (ESRD). Understanding the progressive etiology of DN is critical for the development of effective health policies and interventions. Recent research indicated that polystyrene microplastics (PS-MPs) contaminate our diets and accumulate in various organs, including the liver, kidneys, and muscles. METHODS: In this study, ten-week-old db/db mice and db/m mice were fed. Besides, db/db mice were divided into two groups: PS-MPs group (oral administration of 0.5 µm PS-MPs) and an H2O group, and they were fed for three months. A type II diabetes model was established using db/db mice to investigate the effects of PS-MPs on body weight, blood glucose level, renal function, and renal fibrosis. RESULTS: The results demonstrated that PS-MPs significantly exacerbated various biochemical indicators of renal tissue damage, including fasting blood glucose, serum creatinine, blood urea nitrogen, and blood uric acid. Additionally, PS-MPs worsened the pathological alterations and degree of fibrosis in renal tissue. An increased oxidative stress state and elevated levels of inflammatory cytokines, such as tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and monocyte chemoattractant protein-1 (MCP-1) were identified. Furthermore, PS-MPs significantly enhanced renal fibrosis by inhibiting the transition from epithelial cells to mesenchymal cells, specifically through the inhibition of the TGF-ß/Smad signaling pathway. The expression levels of NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein containing a CARD (ASC), Caspase-1, and cleaved Caspase-1, which are inflammasome proteins, were significantly elevated in the PS-MPs group. CONCLUSION: The findings suggested that PS-MPs could aggravate kidney injury and renal fibrosis in db/db mice by promoting NLRP3/Caspase-1 and TGF-ß1/Smads signaling pathways. These findings had implications for elucidating the role of PS-MPs in DN progression, underscoring the necessity for additional research and public health interventions.

Nanotechnology's frontier in combatting infectious and inflammatory diseases: prevention and treatment.

Inflammation-associated diseases encompass a range of infectious diseases and non-infectious inflammatory diseases, which continuously pose one of the most serious threats to human health, attributed to factors such as the emergence of new pathogens, increasing drug resistance, changes in living environments and lifestyles, and the aging population. Despite rapid advancements in mechanistic research and drug development for these diseases, current treatments often have limited efficacy and notable side effects, necessitating the development of more effective and targeted anti-inflammatory therapies. In recent years, the rapid development of nanotechnology has provided crucial technological support for the prevention, treatment, and detection of inflammation-associated diseases. Various types of nanoparticles (NPs) play significant roles, serving as vaccine vehicles to enhance immunogenicity and as drug carriers to improve targeting and bioavailability. NPs can also directly combat pathogens and inflammation. In addition, nanotechnology has facilitated the development of biosensors for pathogen detection and imaging techniques for inflammatory diseases. This review categorizes and characterizes different types of NPs, summarizes their applications in the prevention, treatment, and detection of infectious and inflammatory diseases. It also discusses the challenges associated with clinical translation in this field and explores the latest developments and prospects. In conclusion, nanotechnology opens up new possibilities for the comprehensive management of infectious and inflammatory diseases.

Microplastics cause hepatotoxicity in diabetic mice by disrupting glucolipid metabolism via PP2A/AMPK/HNF4A and promoting fibrosis via the Wnt/ß-catenin pathway.

In recent years, microplastics (MPs) have gained significant attention as a persistent environmental pollutant resulting from the decomposition of plastics, leading to their accumulation in the human body. The liver, particularly of individuals with type 2 diabetes mellitus (T2DM), is known to be more susceptible to the adverse effects of environmental pollutants. Therefore, to investigate the potential impact of MPs on the liver of diabetic mice and elucidate the underlying toxicological mechanisms, we exposed db/db mice to 0.5 µm MPs for 3 months. Our results revealed that MPs exposure resulted in several harmful effects, including decreased body weight, disruption of liver structure and function, elevated blood glucose levels, impaired glucose tolerance, and increased glycogen accumulation in the hepatic tissue of the mice. Furthermore, MPs exposure was found to promote hepatic gluconeogenesis by perturbing the PP2A/AMPK/HNF4A signaling pathway. In addition, MPs disrupt redox balance, leading to oxidative damage in the liver. This exposure also disrupted hepatic lipid metabolism, stimulating lipid synthesis while inhibiting catabolism, ultimately resulting in the development of fatty liver. Moreover, MPs were found to induce liver fibrosis by activating the Wnt/ß-catenin signaling pathway. Furthermore, MPs influenced adaptive thermogenesis in brown fat by modulating the expression of uncoupling protein 1 (UCP1) and genes associated with mitochondrial oxidative respiration thermogenesis in brown fat. In conclusion, our study demonstrates that MPs induce oxidative damage in the liver, disturb glucose and lipid metabolism, promote hepatic fibrosis, and influence adaptive thermogenesis in brown fat in diabetic mice. These findings underscore the potential adverse effects of MPs on liver health in individuals with T2DM and highlight the importance of further research in this area.

Toxicological effects of microplastics in renal ischemia-reperfusion injury.

The widespread presence of microplastics (MPs) in the environment poses a significant threat to biological survival and human health. However, our understanding of the toxic effects of MPs on the kidneys remains limited. This study aimed to investigate the underlying mechanism of the toxic effects of MPs on the kidneys using an ischemia-reperfusion (IR) mouse model. Four-week-old ICR mice were exposed to 0.5 µm MPs for 12 weeks prior to IR injury. The results showed that MPs exposure could aggravate the IR-induced damage to renal tubules and glomeruli. Although there were no significant changes in blood urea nitrogen and serum creatinine levels 7 days after IR, MPs treatment resulted in a slight increase in both parameters. In addition, the expression levels of inflammatory factors (MCP-1 and IL-6) at the mRNA level, as well as macrophage markers (CD68 and F4/80), were significantly higher in the MPs + IR group than in the Sham group after IR. Furthermore, MPs exposure exacerbated IR-induced renal fibrosis. Importantly, the expression of pyroptosis-related genes, including NLRP3, ASC, GSDMD, cleaved caspase-1, and IL-18, was significantly upregulated by MPs, indicating that MPs exacerbate pyroptosis in the context of renal IR. In conclusion, our findings suggest that MPs exposure can aggravate renal IR-induced pyroptosis by activating NLRP3-GSDMD signaling.

Immunometabolism changes in fibrosis: from mechanisms to therapeutic strategies.

Immune cells are essential for initiating and developing the fibrotic process by releasing cytokines and growth factors that activate fibroblasts and promote extracellular matrix deposition. Immunometabolism describes how metabolic alterations affect the function of immune cells and how inflammation and immune responses regulate systemic metabolism. The disturbed immune cell function and their interactions with other cells in the tissue microenvironment lead to the origin and advancement of fibrosis. Understanding the dysregulated metabolic alterations and interactions between fibroblasts and the immune cells is critical for providing new therapeutic targets for fibrosis. This review provides an overview of recent advances in the pathophysiology of fibrosis from the immunometabolism aspect, highlighting the altered metabolic pathways in critical immune cell populations and the impact of inflammation on fibroblast metabolism during the development of fibrosis. We also discuss how this knowledge could be leveraged to develop novel therapeutic strategies for treating fibrotic diseases.

A Novel Risk Model for lncRNAs Associated with Oxidative Stress Predicts Prognosis of Bladder Cancer.

Background: Oxidative stress (OS) reactions are closely related to the development and progression of bladder cancer (BCa). This project aimed to identify new potential biomarkers to predict the prognosis of BCa and improve immunotherapy. Methods: We downloaded transcriptomic information and clinical data on BCa from The Cancer Genome Atlas (TCGA). Screening for OS genes was statistically different between tumor and adjacent normal tissue. A coexpression analysis between lncRNAs and differentially expressed OS genes was performed to identify OS-related lncRNAs. Then, differentially expressed oxidative stress lncRNAs (DEOSlncRNAs) between tumors and normal tissues were identified. Univariate/multivariate Cox regression analysis was performed to select the lncRNAs for risk assessment. LASSO analysis was conducted to establish a prognostic model. The prognostic risk model could accurately predict BCa patient prognosis and reveal a close correlation with clinicopathological features. We analyzed the principal component analysis (PCA), immune microenvironment, and half-maximal inhibitory concentration (IC50) in the risk groups. Results: We constructed a model containing eight DEOSlncRNAs (AC021321.1, AC068196.1, AC008750.1, SETBP1-DT, AL590617.2, THUMPD3-AS1, AC112721.1, and NR4A1AS). The prognostic risk model showed better results in predicting the prognosis of BCa patients and was strongly correlated with clinicopathological characteristics. We found great agreement between the calibration plots and prognostic predictions in this model. The areas under the receiver operating characteristic (ROC) curve (AUCs) at 1, 3, and 5 years were 0.792, 0.804, and 0.843, respectively. This model also showed good predictive ability regarding the tumor microenvironment and tumor mutation burden. In addition, the high-risk group was more sensitive to eight therapeutic agents, and the low-risk group was more responsive to five therapeutic agents. Sixteen immune checkpoints were significantly different between the two risk groups. Conclusion: Our eight DEOSlncRNA risk models provide new insights into predicting prognosis and clinical progression in BCa patients.

Prognostic significance and identification of basement membrane-associated lncRNA in bladder cancer.

Based on the importance of basement membrane (BM) in cancer invasion and metastasis, we constructed a BM-associated lncRNA risk model to group bladder cancer (BCa) patients. Transcriptional and clinical data of BCa patients were downloaded from The Cancer Genome Atlas (TCGA), and the expressed genes of BM-related proteins were obtained from the BM-BASE database. We download the GSE133624 chip data from the GEO database as an external validation dataset. We screened for statistically different BM genes between tumors and adjacent normal tissues. Co-expression analysis of lncRNAs and differentially expressed BM genes was performed to identify BM-related lncRNAs. Then, differentially expressed BM-related lncRNAs (DEBMlncRNAs) between tumor and normal tissues were identified. Univariate/multivariate Cox regression analysis was performed to select lncRNAs for risk assessment. LASSO analysis was performed to build a prognostic model. We constructed a model containing 8 DEBMlncRNAs (AC004034.1, AL662797.1, NR2F1-AS1, SETBP1-DT, AC011503.2, AC093010.2, LINC00649 and LINC02321). The prognostic risk model accurately predicted the prognosis of BCa patients and revealed that tumor aggressiveness and distant metastasis were associated with higher risk scores. In this model, we constructed a nomogram to assist clinical decision-making based on clinicopathological characteristics such as age, T, and N. The model also showed good predictive power for the tumor microenvironment and mutational burden. We validated the expression of eight lncRNAs using the dataset GSE133624 and two human bladder cancer cell lines (5637, BIU-87) and examined the expression and cellular localization of LINC00649 and AC011503.2 using a human bladder cancer tissue chip. We found that knockdown of LINC00649 expression in 5637 cells promoted the proliferation of 5637 cells.Our eight DEBMlncRNA risk models provide new insights into predicting prognosis, tumor invasion, and metastasis in BCa patients.

Portable visual assay of Bacillus anthracis biomarker based on ligand-functionalized dual-emission lanthanide metal-organic frameworks and smartphone-integrated mini-device.

A single-functionalized ligand single-Ln3+ based dual-emission Ln-MOF fluorescent sensor was established for portable and visual dipicolinic acid (DPA, Bacillus anthracis biomarker) detection. First, a theory calculation-based prediction model was developed for designing single-functionalized ligand single-Ln3+ dual-emission Ln-MOFs. The model consisted of three calculation modules: intramolecular hydrogen bonds, excited state energy levels, and coordination stability with Ln3+ of ligands. Tb3+ and Eu3+ were selected as metal luminescence centers, PTA-X (PTA: p-phthalic acid, X = NH2, CH3, H, OH) with different functional groups as one-step functionalization ligands, and the luminescent feature of four Tb-MOFs and four Eu-MOFs was predicted with the model. Coupled with prediction results and experimental verification results, Tb-PTA-OH was rapidly determined to be the sole dual-emission Ln-MOF. Then, Tb-PTA-OH was applied to DPA detection by ratiometric fluorescence, and an ultra-low limit of detection (13.4 nM) was obtained, which is much lower than the lowest anthrax infectious dose (60 µM). A portable visual assay method based on paper-microchip and smartphone integrated mini-device was further established (limit of qualification 0.48 µM). A new sensing mechanism and a "triple gates" selectivity mechanism to DPA were proposed. This work reveals guidelines for material design and mini-device customization in detecting hazardous substances.

Mechanisms and Strategies to Overcome PD-1/PD-L1 Blockade Resistance in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is characterized by a high rate of systemic metastasis, insensitivity to conventional treatment and susceptibility to drug resistance, resulting in a poor patient prognosis. The immune checkpoint inhibitors (ICIs) represented by antibodies of programmed death receptor 1 (PD-1) and programmed death receptor ligand 1 (PD-L1) have provided new therapeutic options for TNBC. However, the efficacy of PD-1/PD-L1 blockade monotherapy is suboptimal immune response, which may be caused by reduced antigen presentation, immunosuppressive tumor microenvironment, interplay with other immune checkpoints and aberrant activation of oncological signaling in tumor cells. Therefore, to improve the sensitivity of TNBC to ICIs, suitable patients are selected based on reliable predictive markers and treated with a combination of ICIs with other therapies such as chemotherapy, radiotherapy, targeted therapy, oncologic virus and neoantigen-based therapies. This review discusses the current mechanisms underlying the resistance of TNBC to PD-1/PD-L1 inhibitors, the potential biomarkers for predicting the efficacy of anti-PD-1/PD-L1 immunotherapy and recent advances in the combination therapies to increase response rates, the depth of remission and the durability of the benefit of TNBC to ICIs.

Multifunctional nanoscale lanthanide metal-organic framework based ratiometric fluorescence paper microchip for visual dopamine assay.

Dopamine (DA) plays a significant role in the human body and cerebral nervous system, and the accurate and rapid assay of DA is essential for the diagnosis of related diseases. Herein, we proposed a turn-on ratiometric fluorescent DA assay strategy by integrating a specific DA-resorcinol chemical reaction with a multifunctional lanthanide metal-organic framework (Ln-MOF). First, Eu-BTC (1,3,5-benzenetricarboxylic acid) was synthesized and further modified to obtain Cu@Eu-BTC, which simultaneously plays multiple roles such as fluorescence internal standard, nanoreactor, cooperative catalysis effect and color shift enhancement. The Cu@Eu-BTC dispersion-based method exhibits ultra-sensitive (limit of detection, LOD is 0.01 µM) and wide-range linear response (0.04-30 µM) to DA in real serum. More importantly, it has excellent selectivity for DA, even in the presence of epinephrine and norepinephrine analogs. Thus, this method realizes the accurate and precise quantification of DA in serum (recoveries: 98.1%-110.1%, relative standard deviation RSD < 4.6%). Next, Cu@Eu-BTC was prepared into paper microchip, which has good storage stability (RSD < 3.5%, n = 3) in four weeks and achieves point-of-care visual DA assay coupled with smartphone-assisted portable detection device. The MOF paper microchip-based method shows low sample consumption (30 µL), high accuracy and precision for the quantification of DA in serum (recovery of 92.9%-106.2%, RSD < 5.3%), and gets the same assay results as the MOF dispersion-based method (relative error ≤ 6.83%). To our knowledge, this is the first time to propose the catalytic fluorescence turn-on detection strategy of DA based on a MOF paper microchip.

Multifunctional lanthanide metal-organic framework based ratiometric fluorescence visual detection platform for alkaline phosphatase activity.

A turn-on/off ratiometric fluorescence detection platform based on multifunctional lanthanide metal-organic framework (Ln-MOF) and an enzymatic cascade reaction is proposed for alkaline phosphatase (ALP) activity assay. L-phosphotyrosine is hydrolyzed to levodopa (L-dopa) by two steps of enzymatic reaction. L-dopa further reacts with naphthoresorcinol to produce carboxyazamonardine with strong emission at 490 nm. In this process, multifunctional Ln-MOF (Cu@Eu-BTC, BTC is the 1,3,5-benzenetricarboxylic acid) acts not only as a nanozyme to catalyze the fluorogenic reaction between L-dopa and naphthoresorcinol but also as a fluorescence internal standard. The emission of Cu@Eu-BTC at 620 nm is quenched by phosphate anions, and the dual-response ratiometric fluorescence (F490/F620) can be achieved. A good linear relationship was obtained between Δ(F490/F620) and ALP activity in the range 0.3-24 U L-1 with the detection limit of 0.02 U L-1. In addition, a portable assay tube was designed for visual and point-of-care testing of ALP activity by color variation (ratiometric chromaticity). Both the ratiometric fluorescence detection and the visual detection methods were successfully applied to monitor ALP activity in human serum samples with recovery between 95.5%-109.0% and 94.0%-110.1%, and relative standard deviation less than 8.1% and 9.5%, respectively. As far as we know, this is the first report of ALP activity assay assisted by multifunctional Ln-MOF.Graphical abstract.

Rational Design of Dual-Emission Lanthanide Metal-Organic Framework for Visual Alkaline Phosphatase Activity Assay.

The alkaline phosphatase (ALP) activity assay is very significant for disease diagnosis and biomedical research. Lanthanide metal-organic framework (Ln-MOF) based fluorescence sensors have great application potential in ALP activity assays. However, it is critical but challenging to investigate the emission law of Ln-MOFs for revealing rational design principles and selecting an appropriate MOF. Here, we describe a reasonable design strategy for dual-emission Ln-MOFs based on theoretical calculations. This strategy combines Reinhoudt empirical rule, intramolecular charge transfer theory, and aggregation/coordination-induced emission theory; reveals the luminescence law of Ln-MOFs; and provides theoretical guidance for the rational design of dual-emission Ln-MOFs. On the basis of this strategy, we create a dual-emission Tb-MOF fluorescent probe used for ALP activity assay and investigate the detection mechanism. The probe shows ultrasensitive (limit of detection 0.002 mU mL-1) and selective response to ALP, and it suits for point-of-care visual detection coupled with a self-designed portable enzyme activity assay kit and smartphone-assisted visual device. The kit-based visual assay method can accurately quantify the activity of ALP in real serum samples (recovery >93%, and relative error is less than 6.8% compared with the results of fluorescence spectrometer-based method) and consumes only 25 µL of serum. In addition, a logical decoder based on the "dual-key unlocking strategy" is designed, providing a feasible solution for the development of intelligent ALP activity detection equipment. As far as we know, this is the first report of a theoretical calculation-guided versatile design strategy for dual-emission Ln-MOFs and a portable enzyme activity assay kit for visual detection.

Modelling the effects of media coverage and quarantine on the COVID-19 infections in the UK.

A new COVID-19 epidemic model with media coverage and quarantine is constructed. The model allows for the susceptibles to the unconscious and conscious susceptible compartment. First, mathematical analyses establish that the global dynamics of the spread of the COVID-19 infectious disease are completely determined by the basic reproduction number R0. If R0 ≤ 1, then the disease free equilibrium is globally asymptotically stable. If R0 > 1, the endemic equilibrium is globally asymptotically stable. Second, the unknown parameters of model are estimated by the MCMC algorithm on the basis of the total confirmed new cases from February 1, 2020 to March 23, 2020 in the UK. We also estimate that the basic reproduction number is R0 = 4.2816(95%CI: (3.8882, 4.6750)). Without the most restrictive measures, we forecast that the COVID-19 epidemic will peak on June 2 (95%CI: (May 23, June 13)) (Figure 3a) and the number of infected individuals is more than 70% of UK population. In order to determine the key parameters of the model, sensitivity analysis are also explored. Finally, our results show reducing contact is effective against the spread of the disease. We suggest that the stringent containment strategies should be adopted in the UK.