A Self-Assembled Nano-Molecular Glue (Nano-mGlu) Enables GSH/HO-Triggered Targeted Protein Degradation in Cancer Therapy.

Molecular glues are promising protein-degrading agents that hold great therapeutic potential but face significant challenges in rational design, effective synthesis, and precise targeting of tumor sites. In this study, we first overcame some of these limitations by introducing a fumarate-based molecular glue handle onto specific ligands of therapeutic kinases (TBK1, FGFR, and Bcr-Abl), resulting in the effective degradation of these important cancer targets. Despite the broad applicability of the strategy, we unexpectedly discovered potent and widespread cytotoxicity across various cell lines, including noncancerous ones, rendering it less effective in cancer therapy.

KAHA ligation as a platform for the rapid discovery of Protein Tyrosine phosphatase 1B (PTP1B) inhibitors.

We have successfully designed and assembled a 66-member library of protein tyrosine phosphatases (PTP) inhibitor candidates using α-ketoacid-hydroxylamine (KAHA) ligation. Subsequent in situ enzymatic screening revealed a potent hit (IC = 1.67 μM) against PTP1B, which displayed 6.

Genetic determinants of cerebrospinal fluid metabolites and risk of Guillain-Barré syndrome: A bidirectional two-sample Mendelian randomization study.

This study aims to investigate the potential causal relationship between cerebrospinal fluid (CSF) metabolites and Guillain-Barré syndrome (GBS) using a bidirectional two-sample Mendelian randomization (MR) approach. Publicly available summary data from genome-wide association studies (GWAS) were utilized for comprehensive analysis. The CSF metabolite GWAS summary data were extracted from a GWAS conducted by Panyard et al encompassing 338 CSF metabolites in European participants (n = 291).

Genetic determinants of telomere length and risk of aneurysmal subarachnoid hemorrhage: a bidirectional two-sample mendelian randomization study.

Background: Our objective is to investigate the potential causal relationship between telomere length (TL) and aneurysmal subarachnoid hemorrhage (aSAH) and intracranial aneurysms (IAs) by conducting a bidirectional two-sample Mendelian Randomization (MR) study.

Methods: We utilized publicly available summary data from genome-wide association studies (GWAS) for comprehensive analysis. Telomere length-associated data were sourced from the Epidemiology Unit (IEU) GWAS database ( = 472,174), while data pertaining to intracranial aneurysms were derived from a GWAS meta-analysis conducted by Bakker et al.

Rationally designed BCR-ABL kinase inhibitors for improved leukemia treatment via covalent and pro-/dual-drug targeting strategies.

Background: Chronic Myeloid Leukemia (CML) is a blood cancer that remains challenging to cure due to drug resistance and side effects from current BCR-ABL inhibitors. There is an urgent need for novel and more effective BCR-ABL targeting inhibitors and therapeutic strategies to combat this deadly disease.

Method: We disclose an "OH-implant" strategy to improve a noncovalent BCR-ABL inhibitor, PPY-A, by adding a hydroxyl group to its scaffold.

Small Molecule-Induced Post-Translational Acetylation of Catalytic Lysine of Kinases in Mammalian Cells.

Reversible lysine acetylation is an important post-translational modification (PTM). This process in cells is typically carried out enzymatically by lysine acetyltransferases and deacetylases. The catalytic lysine in the human kinome is highly conserved and ligandable.

Kinase Inhibition via Small Molecule-Induced Intramolecular Protein Cross-Linking.

Remarkable progress has been made in the development of cysteine-targeted covalent inhibitors. In kinase drug discovery, covalent inhibitors capable of targeting other nucleophilic residues (i.e.

Characteristics of spatial and temporal variability in the distribution of biological soil crusts on the Loess Plateau, China.

Biological soil crust (biocrust) is widely distributed on the Loess Plateau and plays multiple roles in regulating ecosystem stability and multifunctionality. Few reports are available on the distribution characteristics of biocrust in this region, which limits the assessment of its ecological functions. Based on 388 sampling points in different precipitation zones on the Loess Plateau from 2009 to 2020, we analyzed the coverage, composition, and influencing factors of biocrust across different durations since land abandonment, precipitation levels, topography (slope aspect and position), and utilization of abandoned slopelands (shrubland, forest, and grassland).

Global Reactivity Profiling of the Catalytic Lysine in Human Kinome for Covalent Inhibitor Development.

Advances in targeted covalent inhibitors (TCIs) have been made by using lysine-reactive chemistries. Few aminophiles possessing balanced reactivity/stability for the development of cell-active TCIs are however available. We report herein lysine-reactive activity-based probes (ABPs; 2-14) based on the chemistry of aryl fluorosulfates (ArOSO F) capable of global reactivity profiling of the catalytic lysine in human kinome from mammalian cells.

Inhibition of HSP90 distinctively modulates the global phosphoproteome of developmental stages.

In the unicellular parasites spp., the etiological agents of leishmaniasis, a complex infectious disease that affects 98 countries in 5 continents, chemical inhibition of HSP90 protein leads to differentiation from promastigote to amastigote stage. Recent studies indicate potential role for protein phosphorylation in the life cycle control of .

Meso-aryltellurium-BODIPY-based fluorescence turn-on probe for selective, sensitive and fast glutathione sensing in HepG2 cells.

Glutathione (GSH) as one most abundant thiol, acts as important roles in regulating cellular redox activities, and various diseases are closely related with its abnormal levels. Thus, monitoring intracellular GSH levels is essential for understanding cellular metabolism of many related diseases. In this work, we firstly reported a new fluorescence turn-on sensor, which was capable of selectively, sensitively and rapid sensing GSH over other thiols, especially cysteine and homocysteine in solutions and living cells.

Multitarget inhibitors/probes that target LRRK2 and AURORA A kinases noncovalently and covalently.

Herein, we report a salicylaldehyde-based, reversible covalent inhibitor (A2) that possesses moderate cellular activity against AURKA with a prolonged residence time and shows significant non-covalent inhibition towards LRRK2. Our results indicated that this multitarget kinase inhibitor may be used as the starting point for future development of more potent, selective and dual-targeting covalent kinase inhibitors against AURKA and LRRK2 for mitophagy.

Cell-active, irreversible covalent inhibitors that selectively target the catalytic lysine of EGFR by using fluorosulfate-based SuFEx chemistry.

EGFR signaling is involved in multiple cellular processes including cell proliferation, differentiation and development, making this protein kinase one of the most valuable drug targets for the treatment of non-small cell lung carcinomas (NSCLC). Herein, we describe the design and synthesis of a series of potential covalent inhibitors targeting the catalytically conserved lysine (K745) of EGFR on the basis of Erlotinib, an FDA-approved first-generation EGFR drug. Different amine-reactive electrophiles were introduced at positions on the Erlotinib scaffold proximal to K745 in EGFR.

Recent Advances on PKM2 Inhibitors and Activators in Cancer Applications.

Metabolic reprogramming of cells, from the normal mode of glucose metabolism named glycolysis, is a pivotal characteristic of impending cancerous cells. Pyruvate kinase M2 (PKM2), an important enzyme that catalyzes the final rate-limiting stage during glycolysis, is highly expressed in numerous types of tumors and aids in development of favorable conditions for the survival of tumor cells. Increasing evidence has suggested that PKM2 is one of promising targets for innovative drug discovery, especially for the developments of antitumor therapeutics.

Amplifying the efficacy of ALA-based prodrugs for photodynamic therapy using nanotechnology.

5-aminolevulinic acid (ALA) is a clinically approved prodrug involved in intracellular Heme biosynthesis to produce the natural photosensitizer (PS) Protoporphyrin IX (PpIX). ALA based photodynamic therapy (PDT) has been used to treat various malignant and non-malignant diseases. However, natural ALA has disadvantages such as weak lipophilicity, low stability and poor bioavailability, greatly reducing its clinical performance.

2-Ethynylbenzaldehyde-Based, Lysine-Targeting Irreversible Covalent Inhibitors for Protein Kinases and Nonkinases.

Lysine-targeting irreversible covalent inhibitors have attracted growing interests in recent years, especially in the fields of kinase research. Despite encouraging progress, few chemistries are available to develop inhibitors that are exclusively lysine-targeting, selective, and cell-active. We report herein a 2-ethynylbenzaldehyde (EBA)-based, lysine-targeting strategy to generate potent and selective small-molecule inhibitors of ABL kinase by selectively targeting the conserved catalytic lysine in the enzyme.

Mesopore-encaged active MnOx in nano-silica selectively suppresses lung cancer cells by inducing autophagy.

Autophagy induced by nanomaterials is one of the intracellular catabolic pathways that degrade and recycle the biomacromolecules and damaged organelles in cells and has emerged as a very promising pharmacological target critical to future drug development and anti-cancer therapy. Herein, we developed mesopore-encaged highly-dispersed active cluster-like MnOx in nanosilica entitled MnO-MS, with a size of around 130 nm. Our studies show that MnO-MS could not only obviously induce autophagy in both stable GFP-LC3 HeLa cells and GFP-LC3-mCherry HeLa cells but also could selectively inhibit lung cancer A549 cell growth at 11.

Biodegradable silica nanocapsules enable efficient nuclear-targeted delivery of native proteins for cancer therapy.

Cell nucleus is the desired subcellular organelle of many therapeutic drugs. Although numerous nanomaterial-based methods have been developed which could facilitate nuclear-targeted delivery of small-molecule drugs, few are known to be capable of delivering exogenous native proteins. Herein, we report a convenient and highly robust approach for effective nuclear-targeted delivery of native proteins/antibodies by using biodegradable silica nanocapsules (BSNPs) that were surface-modified with different nuclear localization signals (NLS) peptides.

Enhancing Cutaneous Wound Healing Based on Human Induced Neural Stem Cell-derived Exosomes.

Background: Wound healing of skin is a complicated process. Cutaneous innervation and neurotrophic factors could participate in multiple stages of wound healing. Neurotrophic factors are mainly produced and released by neurons and neural stem cells (NSCs) which could be obtained in large quantities from human-induced pluripotent stem cells (iPSCs) in vitro.

[Reduction of flow velocity by biological soil crust of revegetated grassland in the hilly Loess Plateau, China].

Biological soil crusts (biocrusts) are the common cover in arid and semiarid areas. Together with plants, biocrusts affect runoff and flow velocity. However, few studies have focused on the effects of the co-covering of plant and biocrust (plant+biocrust) on the flow velocity, with a knowledge gap in the study of driving factors for slope erosion in arid and semiarid areas.

A novel TCF-aza-BODIPY-based near-infrared fluorescent probe for highly selective detection of hypochlorous acid in living cells.

Hypochlorous acid/hypochlorite (HOCl/ClO) plays important roles in killing bacterial and causing damage to living tissues, and its abnormal levels could lead to many diseases. Although great efforts have been devoted, fluorescent probes for HOCl/ClO with near-infrared fluorescence, good selectivity/sensitivity, and low background are still important and urgent. In this work, a novel double-bond-linked TCF-aza-BODIPY-based near-infrared fluorescent probe (3) was rationally designed, successfully prepared, and applied for sensing HOCl/ClO in both solutions and living RAW264.

Two-Photon Small-Molecule Fluorogenic Probes for Visualizing Endogenous Nitroreductase Activities from Tumor Tissues of a Cancer Patient.

Nitroreductase (NTR), a common enzymatic biomarker of hypoxia, is widely used to evaluate tumor microenvironments. To date, numerous optical probes have been reported for NTRs detection. Approaches capable of concisely guiding the probe design of NTRs suitable for deep-tissue imaging, however, are still lacking.

Cell-Active, Reversible, and Irreversible Covalent Inhibitors That Selectively Target the Catalytic Lysine of BCR-ABL Kinase.

Despite recent interests in developing lysine-targeting covalent inhibitors, no general approach is available to create such compounds. We report herein a general approach to develop cell-active covalent inhibitors of protein kinases by targeting the conserved catalytic lysine residue using key SuFEx and salicylaldehyde-based imine chemistries. We validated the strategy by successfully developing (irreversible and reversible) covalent inhibitors against BCR-ABL kinase.