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Leucine-rich α-2 glycoprotein 1 (LRG1), a secreted glycoprotein, has been identified as significantly upregulated in renal fibrosis, potentially exacerbating the condition by enhancing TGF-β-Smad3-dependent signaling pathways. Herein, utilizing our developed LRG1-targeting peptide for LRG1 recruitment and lenalidomide for E3 ubiquitin ligase engagement, we developed an advanced proteolysis targeting chimera, ET TAC-2, specifically designed for LRG1 degradation. Our cellular degradation assays validated that ET TAC-2 effectively degraded LRG1 through a proteasome-dependent mechanism, achieving halfmaximal degradation at a concentration of 8.38 μM. Furthermore, anti-fibrotic experiments conducted both in vitro and in vivo revealed that ET TAC-2 efficiently induced LRG1 degradation in fibrotic kidneys. This action effectively inhibited the TGF-β-Smad3 signaling pathway and diminished the secretion of fibrosis-associated proteins, consequently attenuating the progression of renal fibrosis. Our study highlights the pivotal role of LRG1 in renal fibrosis and positions ET TAC-2 as a promising therapeutic candidate for targeted LRG1 intervention. [ABSTRACT FROM AUTHOR]

China's aging demographic poses a challenge for treating prevalent bone diseases impacting life quality. As bone regeneration capacity diminishes with age due to cellular dysfunction and inflammation, advanced biomaterials-based approaches offer hope for aged bone regeneration. This review synthesizes materiobiology principles, focusing on biomaterials that target specific biological functions to restore tissue integrity. It covers strategies for stem cell manipulation, regulation of the inflammatory microenvironment, blood vessel regeneration, intervention in bone anabolism and catabolism, and nerve regulation. The review also explores molecular and cellular mechanisms underlying aged bone regeneration and proposes a database-driven design process for future biomaterial development. These insights may also guide therapies for other age-related conditions, contributing to the pursuit of 'healthy aging'. [ABSTRACT FROM AUTHOR]

Magnetic nanoparticle-mediated mild hyperthermia is an emerging approach for tumor treatment and antitumor immune activation. However, the precise delivery of magnetic hyperthermia nanoagents inside tumor for mild magnetic hyperthermia therapy (MHT) via intravenous administration remains challenging. In this study, we developed a tumor microenvironment (TME)-responsive nanosystem based on cleavable methoxypolyethene glycol (mPEG) and transactivator of transcription (TAT) cell-penetrating peptide dual-decorated Fe3O4 nanocrystals (mPEG@TAT@Fe3O4) and utilized it to facilitate effective magnetic resonance (MR) imaging, tumor MHT, and mild heat-mediated immune stimulation. The as-constructed mPEG@TAT@Fe3O4 exhibited supreme sensitivity to the reducing environment in the TME for detaching the mPEG shell and strongly inhibited the proliferation of tumor cells with exposure to an alternating magnetic field. In vivo experiments in CT26 tumor-bearing mice showed that this nanodelivery system received an enhanced T 2-weighted MR imaging-guided tumor MHT by achieving an 85.5% tumor inhibition rate and induced a magnetic hyperthermia-immune synergistic therapy. Notably, the structure-variable delivery system showed a lower intravenous dosage than previously reported agents at a temperature of 43-44°C induced by MHT. Together with no obvious agent-related adverse events, our study successfully prepared a promising systemic delivery nanomedicine for MR imaging-guided tumor-targeting MHT and provided an attractive method to turn "cold" tumor to "hot". [ABSTRACT FROM AUTHOR]

Safety analysis of engineered nanomaterials (ENMs) presents a formidable challenge regarding environmental health and safety, due to their complicated and diverse physicochemical properties. Although large amounts of data have been published regarding the potential hazards of these materials, we still lack a comprehensive strategy for their safety assessment, which generates a huge workload in decision-making. Thus, an integrated approach is urgently required by government, industry, academia and all others who deal with the safe implementation of nanomaterials on their way to the marketplace. The rapid emergence and sheer number of new nanomaterials with novel properties demands rapid and high-content screening (HCS), which could be performed on multiple materials to assess their safety and generate large data sets for integrated decision-making. With this approach, we have to consider reducing and replacing the commonly used rodent models, which are expensive, time-consuming, and not amenable to high-throughput screening and analysis. In this review, we present a 'Library Integration Approach' for high-content safety analysis relevant to the ENMs. We propose the integration of compositional and property-based ENM libraries for HCS of cells and biologically relevant organisms to be screened for mechanistic biomarkers that can be used to generate data for HCS and decision analysis. This systematic approach integrates the use of material and biological libraries, automated HCS and high-content data analysis to provide predictions about the environmental impact of large numbers of ENMs in various categories. This integrated approach also allows the safer design of ENMs, which is relevant to the implementation of nanotechnology solutions in the pharmaceutical industry. [ABSTRACT FROM AUTHOR]

Aim: To evaluate the advantages of nanomaterial methoxy poly(ethylene glycol)-poly(lactide-co-glycolide) (mPEG-PLGA) encapsulated doxorubicin (D/DOX) and paclitaxel (T/TAX; mPEG-PLGA-DT) over free form of DOXandTAX (DOX/TAX). Materials & methods: Metabonomics was conducted to characterize the systemic metabolic response of allograft breast cancer model mice to mPEG-PLGA-DT and DOX/TAX treatments. Results: Breast tumor growth induced metabolic reprogram in serum and multiple organs. DOX/TAX treatment could ameliorate the elevated energy and nucleotides demands in some organs while mPEG-PLGADT treatment showed outstanding therapeutic outcomes in restoring the metabolic phenotypes of serum and kidney from tumor-bearing mice to the healthy state. Conclusion: This investigation proved the biological advantages of mPEG-PLGA-DT over DOX/TAX in molecular level through the comparison between their metabolic responses in vivo. [ABSTRACT FROM AUTHOR]

BACKGROUND: Weightlessness results in negative physiological changes. Excessive iron in organisms likewise leads to numerous damages. In this study, we investigated the effect of a combination of iron overload and weightlessness simulated by tail-suspending on rats. METHODS: Male Wistar rats were randomly divided into four groups: control (CON), iron overload (10), simulated weightlessness (SW), and iron overload plus simulated weightlessness (10+SW). After the experiment, the rats were evaluated through routine blood, serum ferritin, histology, and micro-computed tomography analyses. RESULTS: As compared to CON, a combination of 10 and SW resulted in a 15.9% loss of rat bodyweight versus treatment with each alone (3.3% in 10,11.7% in SW group). Although iron overload is mainly responsible for an increase in hemoglobin (4.7% in 10 the group) and serum ferritin (71.7% in I0 group) concentration, simulated weightlessness facilitates such increase (5.3% and 118.4% in IO + SW group, respectively). Similarly, iron overload resulted in severe iron deposition on the liver and spleen, and the deposition became more serious in the combined model. In contrast, the simulated weightlessness is mainly responsible for the damage to the femur. DISCUSSION: All the results demonstrated that the combined conditions exhibited a significantly different effect on rats from those with either simulated weightlessness or iron overload alone, and that these different effects are organ-dependent. [ABSTRACT FROM AUTHOR]