Latest Articlesα1-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.
Antibacterial agent of activatable photosensitizer not only has the advantages of traditional photosensitizers, such as good curative effect and low resistance, but also has better selectivity for bacteria and lower toxicity to normal tissues. Limited reports of activatable photosensitizer can be used to treat drug-resistant bacteria. In order to meet this challenge, we designed and synthesized an activatable photosensitizer (Ce-OHOA), which can not only selectively identify methicillin-resistant Staphylococcus aureus (MRSA) with high expression of β-lactamase by fluorescence imaging, but also kill MRSA with less than 10 times the concentration and 10 times the irradiation dose of CySG-2 reported. Ce-OHOA not only combines the dual functions of fluorescence diagnosis and photodynamic therapy, but also selectively acts on bacteria with high expression of β-lactamase and has little toxicity to normal cells. We expect that the study of this activating photosensitizer will provide a new solution for antibacterial photodynamic therapy (aPDT) of drug-resistant bacteria.
As a vital negative regulator of Wnt signaling pathway, human Notum (hNotum) plays a crucial regulatory role in the progression of many human diseases. Deciphering the relevance of hNotum to human diseases requires practical and reliable tools for visualizing hNotum activity in living systems. Herein, an enzyme-activatable fluorogenic tool (IR-783 octanoate) was rationally engineered for sensing and imaging hNotum activity in living systems by integrating computer-aided molecular design and biochemical assays. IR-783 octanoate showed good optical properties, excellent specificity and high binding-affinity towards hNotum (Km = 0.98 µmol/L). IR-783 octanoate could be well up-taken into the cancerous cells or tumors that over-expressed organic anion transporting polypeptides (OATPs), and then hydrolyzed by cellular hNotum to release free IR-783 ketone, which created brightly fluorescent signals around 646 nm. Further investigations showed that IR-783 octanoate achieved a good performance for in-situ functional imaging of hNotum in both living cells, cancerous tissues and organs. It was also found that some SW620 cells with multipolar spindles could be stained by IR-783 octanoate to emit extremely bright signals, suggesting that this agent could be used as a novel visualizing tool for tracing the cells undergoing abnormal cell mitoses. Collectively, this study devises a highly specific fluorogenic tool for in-situ functional imaging of hNotum in living systems, which offers a practical and reliable tool to dynamically track the changes in hNotum activity under various conditions.
Electrochemiluminescence has been developed as a robust analytical technique owing to its intrinsic advantages, such as near-zero background signal noise, wide dynamic ranges, high sensitivity and low cost and simple equipment. ECL luminophore as the critical component to generate light signals plays significant roles in this robust analytical system. Compared with traditional ECL luminophores, near infrared (NIR) ECL luminophores have attracted significant attentions recently due to their negligible autofluorescence, lower background interference and deep tissue penetration. Although substantial progresses have been achieved in exploring novel NIR ECL luminophores and elucidating their roles in addressing diverse challenges, there is still scarce of comprehensive reviews on the development of NIR ECL luminophores so far. In this review, the recent advancements on NIR ECL materials, including inorganic metal complexes, organic small molecules, metal nanoclusters, quantum dots and lanthanide-based materials, have been thoroughly summarized and discussed. In addition, we also provide a comprehensive overview of the challenges and prospects that lie ahead for the future development of NIR ECL luminophores in the future.
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.
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.
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.
Non-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.
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.
The development of enantioselective C-H macrocyclizations to efficiently access structurally diversified macrocycles is highly desirable, but remain a big challenge. Herein, we reported the first rhodium(Ⅲ)-catalyzed asymmetric intramolecular C-H macrocyclization, enabling the efficient synthesis of structurally diverse enantioenriched macrocycles. This robust enantioselective C-H macrocyclization has a broad functional group tolerance, excellent enantioselectivities (up to 98.5:1.5 e.r.) and a mild reaction condition, releasing CO2 as the single by-product. More significantly, the resulting unique enantioenriched 19-membered macrocycle 2f was found to demonstrate a potent in vitro anti-Zika virus (ZIKV) activity without obvious cytotoxicity. Further investigation revealed that the anti-ZIKV activity is presumably attributed to an autophagy inhibition in the early stage of viral infection by down-regulating the expression of autophagy related gene Atg12.
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