Latest ArticlesNon-alcoholic fatty liver disease (NAFLD) is prevalent worldwide as a chronic liver disease that not only gives rise to hepatic complications, but leads to other chronic diseases such as type 2 diabetes and atherosclerosis. The aberrant accumulation of lipid droplets (LDs) in hepatocytes is a prominent signature of NAFLD. However, conventional techniques lack the capability to effectively monitor the dynamic changes in LD levels during NAFLD with living organisms. Hence, it is imperative to develop LD-specific long-wavelength fluorescent probes with high imaging contrast for the in-situ diagnosis of NAFLD. In this study, we synthesized a new LD-selective long-wavelength fluorescent probe, denoted as LD-1, based on the twisted intramolecular charge transfer (TICT) mechanism. The probe exhibits a large Stokes shift and intensive fluorescence emission in nonpolar and viscous solutions. By self-assembling LD-1 with bovine serum albumin (BSA), a biocompatible, long-wavelength fluorescent probe hybrid, LD-1@BSA, was formed, allowing for LDs to be selectively imaged in hepatocytes. Moreover, LD-1@BSA successfully discriminates NAFLD cells before and after drug treatment, and achieves non-invasive and real-time monitoring of LD accumulation in a mouse model of NAFLD.
Chronic kidney disease (CKD) is an increasingly prevalent medical condition associated with high mortality and cardiovascular complications. The intricate interplay between kidney dysfunction and subsequent metabolic disturbances may provide insights into the underlying mechanisms driving CKD onset and progression. Herein, we proposed a large-scale plasma metabolite identification and quantification system that combines the strengths of targeted and untargeted metabolomics technologies, i.e., widely-targeted metabolomics (WT-Met) approach. WT-Met method enables large-scale identification and accurate quantification of thousands of metabolites. We collected plasma samples from 21 healthy controls and 62 CKD patients, categorized into different stages (22 in stages 1–3, 20 in stage 4, and 20 in stage 5). Using LC-MS-based WT-Met approach, we were able to effectively annotate and quantify a total of 1431 metabolites from the plasma samples. Focusing on the 539 endogenous metabolites, we identified 399 significantly altered metabolites and depicted their changing patterns from healthy controls to end-stage CKD. Furthermore, we employed machine-learning to identify the optimal combination of metabolites for predicting different stages of CKD. We generated a multiclass classifier consisting of 7 metabolites by machine-learning, which exhibited an average AUC of 0.99 for the test set. In general, amino acids, nucleotides, organic acids, and their metabolites emerged as the most significantly altered metabolites. However, their patterns of change varied across different stages of CKD. The 7-metabolite panel demonstrates promising potential as biomarker candidates for CKD. Further exploration of these metabolites can provide valuable insights into their roles in the etiology and progression of CKD.
With the increasing demand for personalized and precise treatment, the rapid advancement of synthetic biology technology has inevitably led to the development of nanobiology-based drug delivery systems. Synthetic biology-based drug delivery systems are being increasingly used in the treatment of various diseases. On one hand, synthetic biology technology enables the clever combination of chassis cells, bacteria, and their derivatives with nanomaterials, forming nano-artificial hybrid systems. These systems effectively integrate the functions of both materials, leading to further breakthroughs and optimization of biological functions. On the other hand, synthetic biology strategies guide the self-assembly of modular nanocomponents with biocatalytic or intelligent response functions, resulting in the mimicry of living cell features such as compartmentalization of enzymatic reactions and responsiveness to external stimuli. This provides novel design ideas for the construction of artificial cells. This paper aims to explore the construction and application of biogenic drug delivery systems based on whole cells, cell membrane-encapsulated nanoparticles, exosomes, bacteria, bacterial outer membrane vesicles and artificial cells, taking into account recent advances in this field. The advantages and limitations of current synthetic biology-based nanodrug delivery systems for clinical translation are discussed, and the future prospects of nanotechnology for intelligent drug diagnostic and therapeutic systems are envisioned.
Nanoparticles that employ stimuli-responsive polymeric delivery carriers have emerged as intelligent nanoplatforms with great potential in cancer theranostics, mainly including cancer diagnosis, controlled/triggered drug delivery, and real-time monitoring of therapeutic response. Particularly, tumor microenvironment (TME)-responsive polymeric nanocarriers in response to weak acidity, hypoxia, reactive oxygen species (ROS), glutathione (GSH), or tumor enzymes in the TME show great promise in facilitating tumor accumulation, enhancing tumor penetration, prolonging tumor retention, and achieving controlled drug release, thereby improving the efficiency of tumor therapy. Besides, the combination of chemotherapy and phototherapy presents a promising endeavor for the treatment of tumors, which allows for the integration of the advantages of each treatment modality, addressing the shortcomings of the two methods, and amplifying the efficacy of tumor treatment while reducing adverse reactions. This review focuses on the latest progress in the development of TME-responsive polymeric nanoparticles for synergetic chemo-photo therapy, and discusses the critical challenges and future considerations involved in the fabrication of TME-responsive nanocarriers.
Chemodynamic therapy (CDT) relying on the transformation of endogenous hydrogen peroxide (H2O2) into cytotoxic hydroxyl radicals (•OH) based on the catalysis of Fenton/Fenton-type reactions exhibits great potentiality for cancer treatment. However, the inadequate H2O2 supply and intricate redox homeostasis in tumor microenvironment (TME) severely impair the efficacy of CDT. Herein, we design self-assembled 1,2-distearoyl-sn-glycero-3-phosphoethanolamine conjugated polyethylene glycol (DSPE-PEG)-modified Fe(Ⅲ)-juglone nanoscale coordination polymers (FJP NCPs) as redox homeostasis disruptors for juglone-enhanced CDT. Responding to glutathione (GSH)-rich and acidic TME, the Fe2+/Fe3+-guided CDT and GSH consumption by Fe3+ are activated, resulting in •OH downstream and up-regulation of lipid peroxidation (LPO). In addition, the released juglone not only depletes GSH through Michael addition, but also elevates intracellular H2O2 level for achieving •OH further bursting. With the impressive efficiency of GSH exhaustion and reactive oxygen species (ROS) storm generation, ferroptosis and apoptosis are significantly enhanced by FJP NCPs in vivo. In brief, this facile and efficient design for versatile nanoscale coordination polymers presents a novel paradigm for effectively elevating CDT efficiency and tumor synergistic therapy.
Developing natural nano-platforms with high biocompatibility and natural targeting ability represents great significance for drug delivery. High-density lipoprotein (HDL), a natural lipid-protein complex, plays important roles in physiological activities, particularly in reverse cholesterol transport (RCT) and be closely associated with atherosclerotic cardiovascular diseases. Recent studies have demonstrated that HDLs have the potential to serve as ideal drug carriers. Recombinant HDLs (rHDLs) have been used to encapsulate substances such as small interfering RNA (siRNA), drugs, and contrast agents, fully utilizing the biocompatibility and targeting ability of rHDL in the body and providing new strategies for drug delivery and disease treatment. In this review, we discussed in detail the basic principles of HDL as a drug delivery system, the mechanisms of targeted drug delivery, and several methods for preparing HDL nanoparticles. Afterward, we comprehensively reviewed the applications of HDL as a drug carrier in cardiovascular diseases, cancer treatment (such as glioblastoma, breast cancer, hepatocellular carcinoma and urologic cancers) and some other fields. Finally, we reviewed the therapeutic effects and safety of HDL nanoparticles in clinical studies. Through a review and summary of these research advances, we aim to fully understand the potential of HDL as a drug carrier in clinical applications, providing valuable references and guidance for future research and expedites the translational application of HDL as drug carriers.
Endogenous metabolites play key functions in many important physiological and biochemical processes. The comprehensive in situ detection and direct imaging of metabolites in bio-tissues by matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) is very important for understanding complex and diverse biological processes and has become an essential aspect of spatial omics. In this work, 4-aminoazobenzene (AAB) was successfully screened and optimized as a new negative ion (−)MALDI matrix to enhance the in situ detection and imaging of metabolites in tissues using MALDI-MSI. Obviously, AAB exhibited superior properties in terms of ultraviolet absorption, background ion interference, matrix morphology, and metabolite ionization efficiency. AAB was used for in situ detection and imaging of metabolites in rat brain and germinating Chinese yew seed tissue sections, where 264 and 339 metabolite ion signals were successfully detected and imaged using (-)MALDI-MS, respectively. In addition, high-resolution imaging of mouse eyeball section using MALDI-timsTOF MSI with spatial resolution of up to 10 µm was successfully carried out, showing that AAB is an efficient (-)MALDI matrix for capturing high-resolution images of metabolites in biological tissue sections.
Dual-specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) is the most promising target for diabetes treatment by promoting β-cell proliferation. The desmethylbellidifolin (DMB) as a DYRK1A inhibitor could facilitate β-cell proliferation in vivo and in vitro. However, DMB has the problem of weak binding affinity to DYRK1A, which means that continuous high concentration administration of DMB is effective for the diabetes. In order to solve this problem, we designed and synthesized a series of DMB-based proteolysis targeting chimeras (PROTACs) by taking advantage of the property of PROTAC that induce protein degradation in a cycle-catalytic manner. MDM2-based PROTAC X1–4P-MDM2 was identified as the most active PROTAC molecule. Mechanism research showed that X1–4P-MDM2 formed a ternary complex with DYRK1A and murine double minute 2 (MDM2), and induced the degradation of DYRK1A through the ubiquitin-proteasome system pathway. At a dose much lower than that of DMB, X1–4P-MDM2 still significantly enhanced β-cell proliferation by inhibiting transforming growth factor beta (TGF-β) and promoting the mitogen-activated protein kinases/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway, which may provide a new strategy for the application of DMB in diabetes.
α1-Adrenergic receptor (AR) blockers can be effective for the treatment of benign prostatic hyperplasia/lower urinary tract symptoms (BPH/LUTS), their usage is limited by cardiovascular-related side effects that are caused by the subtype nonselective nature or low selectivity of many current drugs. We previously reported that phenylpiperazine analogues with amide and propane linker were moderate α1D/1A adrenoceptor antagonists and exhibited better anti-BPH effect than lead compound naftopidil (NAF) in vivo, however, with modest α1D/1A-subtype selectivity. Herein, we replaced propane moiety with 2-hydroxypropanol linker and synthesized twenty-seven racemic derivatives with modified aromatic and hetero aromatic groups. Of these new compounds, quinoline surrogate 17 exhibited extremely weak antagonistic affinity on α1B in both cell-based calcium assay and tissue-based functional assay, so that elicited significant α1A/1B and α1D/1B selectivity. Intriguingly, the R enantiomer of 17 preferentially displayed superior anti-BPH effect in rat model compared with S-17, supporting ligand regulates the receptor in a highly stereospecific manner. Finally, the computer-aided modelling research was also performed in order to deeply understand the unique binding mode of R-17 in complex with α1A and the subtype receptor selectivity for R-17 was also rationalized in this study. Taken together, our work enriched the diversity of phenylpiperazines for the treatment of BPH/LUTS, and provided a basis for discovery of α1D/1A-selective ligands.
Nitrogen-doped carbon (N–C) materials have demonstrated exceptional performances in activating peroxymonosulfate (PMS) for environmental remediation. However, accommodating higher nitrogen contents remains challenging in N–C due to the thermodynamic instability of C–N skeleton. In this study, we proposed an innovative epitaxial growth approach to synthesize two-dimensional N–C nanosheets. Leveraging the abundant amino groups supplied by the polymer dots as growing sites, we successfully attained a high nitrogen level and spontaneously introduced abundant structural defects in the carbon framework. The resulting N–C nanosheets exhibited outstanding catalytic activity for the activation of PMS toward selective oxidation of diethyl 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate (1,4-DHP) into diethyl 2,6-dimethylpyridine-3,5-dicarboxylate, which serves as a valuable intermediate in the synthesis of various pharmaceutical compounds. Comprehensive experimental and characterization investigations verified that the nitrogen sites and defects are the primary active sites for PMS activation and selective oxidation of 1,4-DHP. This work offered an efficient approach for the fabrication of high-nitrogen-loading carbon materials for catalytic oxidation reactions.
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