The in situ self‐assembly of exogenous molecules is a powerful strategy for manipulating cellular behavior. However, the direct self‐assembly of photochemically inert constituents into supramolecular ...nano‐photosensitizers (PSs) within cancer cells for precise photodynamic therapy (PDT) remains a challenge. Herein, we developed a glycosylated Aza‐BODIPY compound (LMBP) capable of self‐assembling into J‐aggregate nanofibers in situ for cell membrane destruction and type I PDT. LMBP selectively entered human hepatocellular carcinoma HepG2 cells and subsequently self‐assembled into intracellular J‐aggregate nanovesicles and nanofibers through supramolecular interactions. Detailed studies revealed that these J‐aggregate nanostructures generated superoxide radicals (O2−⋅) exclusively through photoinduced electron transfer, thus enabling effective PDT. Furthermore, the intracellular nanofibers exhibited an aggregation‐induced retention effect, which resulted in selective toxicity to HepG2 cells by disrupting their cellular membranes and synergizing with PDT for powerful tumor suppression efficacy in vivo.
We designed a lactosylated Aza‐BODIPY compound that self‐assembles in situ to form J‐aggregate nanofibers acting as type I photosensitizers. The J‐aggregate nanofibers exhibited remarkable superoxide anion radical (O2−.) generation efficiency, the ability to damage the tumor cell membrane, and long‐term retention at tumor sites. This efficient synergistic therapeutic effect was confirmed in HepG2 cells and tumor‐bearing mice.
The homeostatic link between oxidative stress and autophagy plays an important role in cellular responses to a wide variety of physiological and pathological conditions. However, the regulatory ...pathway and outcomes remain incompletely understood. Here, we show that reactive oxygen species (ROS) function as signaling molecules that regulate autophagy through ataxia‐telangiectasia mutated (ATM) and cell cycle checkpoint kinase 2 (CHK2), a DNA damage response (DDR) pathway activated during metabolic and hypoxic stress. We report that CHK2 binds to and phosphorylates Beclin 1 at Ser90/Ser93, thereby impairing Beclin 1‐Bcl‐2 autophagy‐regulatory complex formation in a ROS‐dependent fashion. We further demonstrate that CHK2‐mediated autophagy has an unexpected role in reducing ROS levels via the removal of damaged mitochondria, which is required for cell survival under stress conditions. Finally, CHK2−/− mice display aggravated infarct phenotypes and reduced Beclin 1 p‐Ser90/Ser93 in a cerebral stroke model, suggesting an in vivo role of CHK2‐induced autophagy in cell survival. Taken together, these results indicate that the ROS‐ATM‐CHK2‐Beclin 1‐autophagy axis serves as a physiological adaptation pathway that protects cells exposed to pathological conditions from stress‐induced tissue damage.
Synopsis
Whether hypoxia and nutrient starvation are coupled to cellular autophagy remains unclear. Here, DNA damage response kinases ATM and CHK2 are shown to trigger autophagy in response to reactive oxygen species (ROS) accumulation, suggesting a novel physiological adaptation pathway toward metabolic stress.
Depletion of CHK2 or ATM impairs oxidative stress‐induced autophagy in MEFs.
CHK2 binds and phosphorylates Beclin1 at Ser90/Ser93, suppressing Beclin1‐Bcl‐2 autophagy regulatory complex formation.
CHK2‐induced autophagy limits intracellular ROS levels by clearing damaged mitochondria.
CHK2‐induced autophagy protects against cell death and tissue damage following cerebral ischemia.
ROS accumulation activates protective autophagy to prevent stress‐induced tissue damage.
In this work, we established catalytic asymmetric 4+1 cyclization of ortho‐quinone methides (o‐QMs) with 3‐chlorooxindoles and a catalytic asymmetric domino oxidation/4+1 cyclization reaction of ...2‐alkylphenols with 3‐chlorooxindoles, which constructed a spirooxindole‐based 2,3‐dihydrobenzofuran scaffold in good yield (up to 97%), with excellent diastereoselectivity (up to >95:5 dr) and high enantioselectivity (up to 99% ee). This work is not only the first highly enantioselective 4+1 cyclization of o‐QMs but has also realized the first catalytic asymmetric domino 4+1 cyclization of o‐QMs. In addition, both of the reactions provide efficient stereoselective methods for constructing spirooxindole‐based 2,3‐dihydrobenzofuran scaffolds with optical purity.
Leucine aminopeptidase (LAP) is a kind of proteolytic enzymes and associated closely with pathogenesis of cancer and liver injury. Accurate detection of LAP activity with high sensitivity and ...selectivity is imperative to detect its distribution and dynamic changes for understanding LAP’s function and early diagnosing the disease states. However, fluorescent detection of LAP in living systems is challenging. To date, rarely fluorescent probes have been reported for imaging LAP in vivo. In this study, a novel probe (TMN-Leu) was developed by conjugating a near-infrared dicyanoisophorone derivative fluorophore with LAP activatable l-leucine amide moiety for the first time. TMN-Leu featured large Stokes shift (198 nm), favorable water solubility, ultrasensitive sensitivity (detection limit of ∼0.38 ng/mL), good specificity, excellent cell membrane permeability, low toxicity, and a prominent near-infrared emission (658 nm) in response to LAP. TMN-Leu has been successfully applied to track LAP of cancer cells and normal cells, monitor LAP changes in different disease models, and rapidly evaluate LAP inhibitor in cell-based assay. Notably, this probe firstly revealed that HCT116 cells with higher LAP activity were more invasive than LAP siRNA transfected HCT116 cells, suggesting that LAP might serve as an indicator reflecting the intrinsic invasion ability of cancer cells. Finally, TMN-Leu was also employed for in vivo real-time imaging LAP in living tumor-bearing nude mice with low background interference. All together, our probe possesses potential value as a promising tool for diagnostic application, cell-based screening inhibitors and in vivo real-time tracking enzymatic activity in preclinical applications.
•Before rockburst, the sudden rise of MS energy and the lower level of event count.•When rockburst, peak value of fault total area, the lower b value, and |Z|>2.•When rockburst, the largest energy ...ratio in the dominant low-frequency band.•Before rockburst, abnormal cluster of sources and high-energy events congregation.•Prior to rockburst, the sudden drop of EME amplitude indicating macro-fracture.
Summary of main observation and conclusion
A new class of indole‐based allylic donors have been designed and developed for palladium‐catalyzed decarboxylative allylations. In addition, the first ...application of these indole‐based allylic donors in palladium‐catalyzed decarboxylative 3+2 cycloaddition and allylic amination has been achieved by reacting with isocyanates and sulfonyl amines, respectively. This approach represents the first design of indole‐based allylic donors, which is helpful for settling the challenge of designing and developing new class of heterocycle‐based allylic donors for Pd‐catalyzed decarboxylative allylation reactions. Moreover, the application of this new class of allylic donors in cycloadditions and substitutions will add new contents to the research field of decarboxylative allylation.
A new class of indole‐based allylic donors have been designed and applied in palladium‐catalyzed decarboxylative 3+2 cycloaddition and allylic amination.
Global climate change has a significant effect on extreme environments and a profound influence on species survival. However, little is known of the genome-wide pattern of livestock adaptations to ...extreme environments over a short time frame following domestication. Sheep (Ovis aries) have become well adapted to a diverse range of agroecological zones, including certain extreme environments (e.g., plateaus and deserts), during their post-domestication (approximately 8-9 kya) migration and differentiation. Here, we generated whole-genome sequences from 77 native sheep, with an average effective sequencing depth of ∼5× for 75 samples and ∼42× for 2 samples. Comparative genomic analyses among sheep in contrasting environments, that is, plateau (>4,000 m above sea level) versus lowland (<100 m), high-altitude region (>1500 m) versus low-altitude region (<1300 m), desert (<10 mm average annual precipitation) versus highly humid region (>600 mm), and arid zone (<400 mm) versus humid zone (>400 mm), detected a novel set of candidate genes as well as pathways and GO categories that are putatively associated with hypoxia responses at high altitudes and water reabsorption in arid environments. In addition, candidate genes and GO terms functionally related to energy metabolism and body size variations were identified. This study offers novel insights into rapid genomic adaptations to extreme environments in sheep and other animals, and provides a valuable resource for future research on livestock breeding in response to climate change.
γ-Glutamyltranspeptidase (GGT) plays critical roles in regulating various physiological/pathophysiological processes including the intracellular redox homeostasis. However, an effective fluorescent ...probe for dissecting the relationships between GGT and oxidative stress in vivo remains largely unexplored. Herein, we present a light-up fluorescent probe (DCDHF-Glu) with long wavelength emission (613 nm) for the highly sensitive and selective detection of GGT using dicyanomethylenedihydrofuran derivative as the fluorescent reporter and γ-glutamyl group as the enzyme-active trigger. DCDHF-Glu is competent to real-time image endogenous GGT in live cells and mice. In particular, DCDHF-Glu enables the direct real-time visualization of the upregulation of GGT under drug-induced oxidative stress in the HepG2 cells and the LO2 cells, as well as in vivo, vividly implying its excellent capacity in elucidation of GGT function in GGT-related biological events.
The contribution of extracellular polymeric substances (EPS), including loosely bound EPS (LB-EPS) and tightly bound EPS (TB-EPS), to the aggregation of both aerobic and anaerobic sludge is explored ...using the extended DLVO theory. It is observed that the aggregation abilities of both sludge samples decrease with the extraction of LB-EPS and TB-EPS, implying the crucial roles of EPS in sludge aggregation. Furthermore, through analyzing the interaction energy curves of sludge before and after the EPS extraction using the extended DLVO theory, it is found that both LB-EPS and TB-EPS have a substantial contribution to the sludge aggregation. The interaction energy of LB-EPS is always negative, suggesting that the LB-EPS always display a positive effect on the sludge aggregation. On the other hand, the interaction energy of TB-EPS is not always negative, depending on the separation distance between sludge cells. These results imply that the LB-EPS and TB-EPS have different contributions to the sludge aggregation.
During the past decades, the interaction between boronic acids-functionalized sensors and saccharides is of great interest in the frontier domain of the interdiscipline concerning both biology and ...chemistry. Various boronic acid-based sensing systems have been developed to detect saccharides and corresponding derivatives in vitro as well as in vivo, which embrace unimolecular sensors, two-component sensing ensembles, functional assemblies, and boronic acid-loaded nanomaterials or surfaces. New sensing strategies emerge in endlessly with excellent selectivity and sensitivity. In this review, several typical sensing systems were introduced and some promising examples were highlighted to enable the deep insight of saccharides sensing on the basis of boronic acids.
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•Unimolecular sensors including monoboronic acid and di-/multi-boronic acids were designed for detecting saccharides.•Two-component sensing systems were fabricated for saccharides discrimination.•Assembly-based sensing systems was well explored for saccharides recognition.•Boronic acid-functionalized nanomaterials and surfaces have been achieved for saccharides sensing.
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![Catalytic Asymmetric [4+1] ...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/1615-4150/small "Catalytic Asymmetric [4+1] Cyclization of ortho‐Quinone Methides with 3‐Chlorooxindoles")
