Two novel C(sp3)−H functionalization of inert alkanes and visible‐light promoted oxidation decarboxylation of N‐hydroxyphthalimide (NHP) esters to access polycyclic quinazolinones have been ...described. These methods do not involve metal catalysts and are carried out in water or water/DMSO media. The wide substrate scope, even including the seven‐membered ring under mild reaction conditions, demonstrate the practicability of these strategies.
This work describes the cleavage of the C(sp3)−H bond of inert alkanes and the visible‐light promoted oxidation decarboxylation of NHP‐esters to form alkyl radicals, which then efficiently synthesize valuable polycyclic quinazolinones through radical addition and cyclization. Both methods were carried out in water or water/DMSO media without metal catalysts with good functional group compatibility.
The fast development of single-particle cryogenic electron microscopy (cryo-EM) has made it more feasible to obtain the 3D structure of well-behaved macromolecules with a molecular weight higher than ...300 kDa at ~3 Å resolution. However, it remains a challenge to obtain the high-resolution structures of molecules smaller than 200 kDa using single-particle cryo-EM. In this work, we apply the Cs-corrector-VPP-coupled cryo-EM to study the 52 kDa streptavidin (SA) protein supported on a thin layer of graphene and embedded in vitreous ice. We are able to solve both the apo-SA and biotin-bound SA structures at near-atomic resolution using single-particle cryo-EM. We demonstrate that the method has the potential to determine the structures of molecules as small as 39 kDa.
Tumour heterogeneity remains a major challenge in cancer therapy owing to the different susceptibility of cells to chemotherapy within a solid tumour. Cancer stem-like cells (CSCs), which reside in ...hypoxic tumour regions, are characterized by high tumourigenicity and chemoresistance and are often responsible for tumour progression and recurrence. Here we report a nanotherapeutic strategy to kill CSCs in tumours using nanoparticles that are co-loaded with the differentiation-inducing agent, all-trans retinoic acid, and the chemotherapeutic drug, camptothecin. All-trans retinoic acid is released under hypoxic conditions, leading to CSC differentiation in the hypoxic niche. In differentiating CSC, the reactive oxygen species levels increase, which then causes the release of camptothecin and subsequent cell death. This dual strategy enables controlled drug release in CSCs and reduces stemness-related drug resistance, enhancing the chemotherapeutic response. In breast tumour mouse models, treatment with the nanoparticles suppresses tumour growth and prevents post-surgical tumour relapse and metastasis.
Chemodivergent tandem radical cyclization offers exciting possibilities for the synthesis of structurally diverse cyclic compounds. Herein, we revealed a chemodivergent tandem cyclization of ...alkene‐substituted quinazolinones under metal‐ and base‐free conditions, this transformation is initiated by alkyl radicals produced from oxidant‐induced α‐C(sp3)−H functionalization of alkyl nitriles or esters. The reaction resulted in the selective synthesis of a series of mono‐ and di‐alkylated ring‐fused quinazolinones by modulating the loading of oxidant, reaction temperature, and reaction time. Mechanistic investigations show that the mono‐alkylated ring‐fused quinazolinones is constructed by the key process of 1,2‐hydrogen shift, whereas the di‐alkylated ring‐fused quinazolinones is mainly achieved through crucial steps of resonance and proton transfer. This protocol is the first example of remote second alkylation on the aromatic ring via α‐C(sp3)−H functionalization and difunctionalization achieved by association of two unsaturated bonds in radical cyclization.
A novel method for preparing mono‐ and di‐alkylated ring‐fused quinazolinones from alkene‐substituted quinazolinones via chemodivergent tandem radical cyclization under metal‐ and base‐free conditions has been established.
•Heat transfer characteristics of the twisted petaloid spiral wound tube (TPSWT) are investigated.•Expression of heat transfer exergy loss number (HTELN) is derived.•Characteristics of the HTELN is ...studied.•Correlation of the HTELN for the TPSWT is formulated.
The spiral flow motivates an extra centrifugal force inducing the secondary flow to effectively enhance the heat transfer performance of spirally wound tubes (SWTs). In this research, the flow and heat transfer characteristics of twisted petaloid spirally wound tube (TPSWT) basis of exergy theory was numerically analyzed, which integrates the technologies of spiral coil, petaloid section and twisted channel. Firstly, the flow and heat transfer characteristics of the TPSWT are numerically investigated. Secondly, the heat transfer exergy loss number (HTELN, ζHT) is proposed. Furthermore, the relationship between η (heat transfer effectiveness) and ζHT is investigated. Finally, the correlations for Nupetal, η and ζHT in the form of classical power–law expression are calculated. The results show that, the secondary flow induced by the integration of the centrifugal force and the torsional force destroying the steady flow state, which enhances the heat transfer performance; ζHT can describe the heat transfer performance in 2 aspects, one is for the heat transfer irreversible loss, the other one is for the heat transfer efficiency; the predicted values of the regression functions are well aligned with the numerical calculated data (6.73% for Nupetal; 1.68% for η; 0.38% for ζHT).
Sepsis is a life‐threatening disease resulted from a dysregulated host immune response to bacterial infections, continuing to cause high morbidity and mortality worldwide. Despite discoveries of many ...potential therapeutic targets, effective treatments of sepsis are lacking. Here, a strategy is reported to target infectious microenvironments (IMEs) via bioresponsive nanoparticles that simultaneously eliminate bacteria and alleviate the host inflammation response, thus managing sepsis in mice. The nanoparticle is made of copolymers sensitive to pH and bacterial enzymes to self‐assemble into a micelle loaded with both an antibiotic (ciprofloxacin) and an anti‐inflammatory agent ((2‐(aminocarbonyl)amino‐5‐(4‐fluorophenyl)‐3‐thiophenecarboxamide). In addition, the nanoparticle is conjugated with intercellular adhesion molecule‐1 antibodies to target IMEs. Nanoparticle targeting to IMEs and local cues as triggers to deliver therapeutics in on‐demand manners is demonstrated using an acute lung bacterial infection mouse model. In the sepsis mouse model induced by peritonitis at a lethal dose of bacterial invasion, it is shown that concurrently targeting pathogens and excessive inflammation pathways is valuable to manage the sepsis. The study illustrates not only the development of a new delivery system but also the mechanism‐based therapy of nanomedicine for infectious diseases.
Stimuli‐responsive nanoparticles loaded with antibiotic and anti‐inflammatory agents can specifically target infection sites via binding to intercellular adhesion molecule‐1 (ICAM‐1) expressed on inflamed endothelium. The nanoparticles are composed of pH/enzyme‐responsive copolymers and anti‐mouse ICAM‐1 antibody, and drug release is triggered by infectious microenvironments. The studies show concurrently eliminating pathogens and mitigating host inflammation responses are valuable to manage sepsis.
Tributyltin (TBT), an organotin compound frequently detected in the coastal environments, poses a threat to aquatic organisms. The lined seahorse (Hippocampus erectus) is a vulnerable species found ...in nearshore water habitats. The mechanisms by which this fish responds to TBT exposure are not yet fully understood. Histological, biochemical, and transcriptional analyses were conducted, and the results showed that 60 days of exposure to 50 and 500 ng/L TBT caused significant tin accumulation and liver damage to seahorses. Antioxidant defenses and immune responses to TBT exposure in the livers of seahorses were further investigated. The enzymatic activity of superoxide dismutase and malondialdehyde content increased, while catalase activity decreased. Transcriptomic analysis revealed that a series of genes involved in the antioxidant defense system were highly induced to protect the hepatic cells from oxidative damage. TBT exposure also resulted in the induction of genes associated with immune and inflammatory processes, representing a stress response to combat the adverse environmental conditions in the exposed seahorses. Furthermore, seahorses showed an increased health risk, according to the elevation of the expression of genes with tumor-promoting effects, when exposed to TBT. These findings contribute to our understanding of the adverse effects of TBT exposure on seahorses, and their potential defense mechanisms.
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•Tributyltin exposure caused seahorse liver damage and dysfunction.•Tributyltin disturbed redox balance and changed antioxidant defense in seahorses.•Tributyltin exposure increased the risk of tumorigenesis in seahorse livers.
PM2.5 is recently identified as a kind of material possessing severe biohazard. It can enter human body and exerts pathological effects on lung, eyes, and the central nervous system (CNS). Maternal ...exposure to PM2.5 can affect neural development and cause cognitive decline in offspring, with the underlying mechanisms unclear, however. The inflammasome monitors and responds to biological stressors, with HMGB1-NLRP3 inflammatory axis as an essential pathophysiological player outside the brain. The present work is to investigate its role in cognitive impairment induced by gestational exposure to PM2.5 in mice offspring. We found that HMGB1-NLRP3 pathway was activated in the hippocampus of mice offspring by gestational exposure to PM2.5 in a dose-dependent manner, with protein levels of HMGB1, NLRP3, and cleaved caspase-1 as approximately three times as high as those of control. And down-regulating HMGB1 during pregnancy could alleviate the resultant impairment on learning and working memory as well as hippocampal neurons, up-regulate the synapse related proteins of SYP and PSD-95 and correct the increased expression of 5-HT2A to comparable levels to control, as well as inhibiting the activation of microglia and decreasing the expression of HMGB1 and Iba1/HMGB1 double positive cells in the hippocampus of mice offspring. Meanwhile, protein levels of NLRP3, cleaved caspase-1, IL-1β and IL-18, as well as TLR4, phosphorylated NF-κB, and MAPKs, were almost down-regulated to those of control. Therefore, HMGB1 intervention inhibits the NLRP3 inflammasome mediated hippocampal inflammatory response through TLR4/MAPKs/NF-κB signaling pathway, alleviating PM2.5-induced cognitive dysfunction. Further in vitro results suggest that PM2.5 can activate microglia and HMGB1-NLRP3 inflammatory axis. Pretreatment with HMGB1 inhibitor significantly reduced the phosphorylation of MAPKs and NF-κB, and inhibited the inflammatory response mediated by NLRP3 inflammasome similarly to those in vivo. These results suggest that PM2.5 exposure promotes the inflammatory response in hippocampus mediated by HMGB1-NLRP3 inflammatory axis in microglia, resulting in cognitive dysfunction in offspring, which could be alleviated by simultaneous HMGB1 suppression. These findings provide a theoretical basis for preventing cognitive impairment in offspring caused by environmental pollution during pregnancy.
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•PM2.5 activates the HMGB1-NLRP3 inflammatory axis in microglia cells.•HMGB1 intervention inhibits HMGB1-TLR4/MAPKs/NF-κb-NLRP3 pathway induced by PM2.5.•HMGB1 intervention alleviates cognitive dysfunction induced by PM2.5 exposure.•HMGB1 inhibition allays PM2.5-induced hippocampal inflammation and neuronal damage.
L-aspartate (Asp) serves as a central building block, in addition to being a constituent of proteins, for many metabolic processes in most organisms, such as biosynthesis of other amino acids, ...nucleotides, nicotinamide adenine dinucleotide (NAD), the tricarboxylic acid (TCA) cycle and glycolysis pathway intermediates, and hormones, which are vital for growth and defense. In animals and humans, lines of data have proved that Asp is indispensable for cell proliferation. However, in plants, despite the extensive study of the Asp family amino acid pathway, little attention has been paid to the function of Asp through the other numerous pathways. This review aims to elucidate the most important aspects of Asp in plants, from biosynthesis to catabolism and the role of Asp and its metabolic derivatives in response to changing environmental conditions. It considers the distribution of Asp in various cell compartments and the change of Asp level, and its significance in the whole plant under various stresses. Moreover, it provides evidence of the interconnection between Asp and phytohormones, which have prominent functions in plant growth, development, and defense. The updated information will help improve our understanding of the physiological role of Asp and Asp-borne metabolic fluxes, supporting the modular operation of these networks.
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