Carbon Free Radical (R∙) Inactivates NF-κB for Radical Capping Therapy.

Inactivating hyperactivated transcription factors can overcome tumor therapy resistance, but their undruggable features limit the development of conventional inhibitors. Here, we report that carbon-centered free radicals (R∙) can inactivate NF-κB transcription by capping the active sites in both NF-κB and DNA. We construct a type of thermosensitive R∙ initiator loaded amphiphilic nano-micelles to facilitate intracellular delivery of R∙. At a temperature of 43°C, the generated R∙ engage in electrophilic radical addition towards double bonds in nucleotide bases, and simultaneously cap the sulfhydryl residues in NF-κB through radical chain reaction. As a result, both NF-κB nuclear translocation and NF-κB-DNA binding are suppressed, leading to a remarkable NF-κB inhibition of up to 94.1%. We have further applied R∙ micelles in a clinical radiofrequency ablation tumor therapy model, showing remarkable NF-κB inactivation and consequently tumor metastasis inhibition. Radical capping strategy not only provides a method to solve the heat-sink effect in clinic tumor hyperthermia, but also suggests a new perspective for controllable modification of biomacromolecules in cancer therapy.

Isolation and biological activity of natural chalcones based on antibacterial mechanism classification.

Bacterial infection, which is still one of the leading causes of death in humans, poses an enormous threat to the worldwide public health system. Antibiotics are the primary medications used to treat bacterial diseases. Currently, the discovery of antibiotics has reached an impasse, and due to the abuse of antibiotics resulting in bacterial antibiotic resistance, researchers have a critical desire to develop new antibacterial agents in order to combat the deteriorating antibacterial situation. Natural chalcones, the flavonoids consisting of two phenolic rings and a three-carbon α, ß-unsaturated carbonyl system, possess a variety of biological and pharmacological properties, including anti-cancer, anti-inflammatory, antibacterial, and so on. Due to their potent antibacterial properties, natural chalcones possess the potential to become a new treatment for infectious diseases that circumvents existing antibiotic resistance. Currently, the majority of research on natural chalcones focuses on their synthesis, biological and pharmacological activities, etc. A few studies have been conducted on their antibacterial activity and mechanism. Therefore, this review focuses on the antibacterial activity and mechanisms of seventeen natural chalcones. Firstly, seventeen natural chalcones have been classified based on differences in antibacterial mechanisms. Secondly, a summary of the isolation and biological activity of seventeen natural chalcones was provided, with a focus on their antibacterial activity. Thirdly, the antibacterial mechanisms of natural chalcones were summarized, including those that act on bacterial cell membranes, biological macromolecules, biofilms, and quorum sensing systems. This review aims to lay the groundwork for the discovery of novel antibacterial agents based on chalcones.

Hippocampal transcriptome analysis reveals mechanisms of cognitive impairment in beagle dogs with type 1 diabetes.

Diabetic encephalopathy is a common complication of type 1 diabetes. However, there have been few studies on cognitive impairment and hippocampal damage in type 1 diabetes mellitus (T1DM) using dogs as experimental animals. To investigate the effects of diabetes on the CNS, 40 adult beagles were divided into streptozotocin/alloxan type 1 diabetes model and control groups. The duration of diabetes in the model group was 120 days. A cognitive dysfunction scale was used to assess cognitive function. Hematoxylin and eosin and Golgi-Cox staining methods were used to observe morphological damage to the hippocampus. Transcriptomics was used to investigate differential gene expression in the hippocampus. The results showed that the cognitive dysfunction score of the model group was significantly higher than that of the control group. In addition, the number of normal neurons, the complexity of dendritic morphology, and the density of dendritic spines were decreased in the hippocampus of diabetic dogs. A total of 672 differentially expressed genes (DEGs) were identified, 289 of which were upregulated, and 383 were downregulated. Modified genes included DBH, IGFBP2, AVPR1A, and DRAXIN. In conclusion, type 1 diabetic dogs exhibit cognitive dysfunction. The DEGs were mainly enriched in metabolic, PI3K-Akt signaling, and neuroactive ligand-receptor interaction pathways.

N-acetylcysteine alleviates oxidative stress and apoptosis and prevents skeletal muscle atrophy in type 1 diabetes mellitus through the NRF2/HO-1 pathway.

AIMS: Type 1 diabetes mellitus (T1DM) has been linked to the occurrence of skeletal muscle atrophy. Insulin monotherapy may lead to excessive blood glucose fluctuations. N-acetylcysteine (NAC), a clinically employed antioxidant, possesses cytoprotective, anti-inflammatory, and antioxidant properties. The objective of our study was to evaluate the viability of NAC as a supplementary treatment for T1DM, specifically regarding its therapeutic and preventative impacts on skeletal muscle. MAIN METHODS: Here, we used beagles as T1DM model for 120d to explore the mechanism of NRF2/HO-1-mediated skeletal muscle oxidative stress and apoptosis and the therapeutic effects of NAC. Oxidative stress and apoptosis related factors were analyzed by immunohistochemistry, immunofluorescence, western blotting, and RT-qPCR assay. KEY FINDINGS: The findings indicated that the co-administration of NAC and insulin led to a reduction in creatine kinase levels, preventing weight loss and skeletal muscle atrophy. Improvement in the reduction of muscle fiber cross-sectional area. The expression of Atrogin-1, MuRF-1 and MyoD1 was downregulated, while Myh2 and MyoG were upregulated. In addition, CAT and GSH-Px levels were increased, MDA levels were decreased, and redox was maintained at a steady state. The decreased of key factors in the NRF2/HO-1 pathway, including NRF2, HO-1, NQO1, and SOD1, while KEAP1 increased. In addition, the apoptosis key factors Caspase-3, Bax, and Bak1 were found to be downregulated, while Bcl-2, Bcl-2/Bax, and CytC were upregulated. SIGNIFICANCE: Our findings demonstrated that NAC and insulin mitigate oxidative stress and apoptosis in T1DM skeletal muscle and prevent skeletal muscle atrophy by activating the NRF2/HO-1 pathway.

Sunitinib-based Proteolysis Targeting Chimeras (PROTACs) reduced the protein levels of FLT-3 and c-KIT in leukemia cell lines.

Proteolysis Targeting Chimeras (PROTACs) based on multi-target inhibitors have been reported several times recently. The advantages of PROTACs technology and the synergistic mechanism of multi-target drugs endow this class of protein degraders with special research significance. Herein, twelve new PROTACs based on Sunitinib and VHL-ligand were synthesized and evaluated for their in vitro anticancer activities. Among them, PROTACs 5 (IC50 = 2.9 ± 1.5 µM) exhibited the most significant antiproliferative activity against HL-60 cells. Western blot results showed that PROTAC 5 reduced the protein levels of FLT-3 and c-KIT in HL-60 cells, and induced the degradation of FLT-3 via the ubiquitin-proteasome system. Moreover, PROTACs 5 and 6 reduced the protein levels of FLT-3 in K562 cells. These results suggest that PROTAC 5 has the potential for further research, especially in combination with small molecule kinase inhibitors to study multidrug resistance of tyrosine kinase inhibitors in cancer treatment.

Progress of isolation, chemical synthesis and biological activities of natural chalcones bearing 2-hydroxy-3-methyl-3-butenyl group.

Chalcones have a three-carbon α,ß-unsaturated carbonyl system composed of two phenolic rings. Many chalcones have shown broad spectrum of biological activities with clinical potentials against various diseases. They are usually abundant in seeds, fruit skin, bark and flowers of most edible plants. Among them, chalcones bearing 2-hydroxy-3-methyl-3-butenyl (HMB) group have been reported several times in the past few decades due to their novel scaffolds and numerous interesting biological activities. In this paper, we reviewed the isolation of twelve natural chalcones and a natural chalcone-type compound bearing 2-hydroxy-3-methyl-3-butenyl group discovered so far, and reviewed their synthesis methods and biological activities reported in the literature. We anticipate that this review will inspire further research of natural chalcones.

Structural modification and antibacterial property studies of natural chalcone sanjuanolide.

Clinical infections arise from multidrug-resistant bacteria and pose a serious threat to human and global public health. Moreover, due to very few antibiotics being discovered, there is an urgent need to develop new antibacterial agents to combat antimicrobial resistance challenges. In this study, a series of new chalcone derivatives bearing a 3'-hydroxyisoprenyl moiety were prepared to employ Claisen-Schmidt condensation as a key step by combinatorial chemistry, and overall yields of these novel derivatives are in the range of 28-68% in the two-step reaction. Sanjuanolide and the synthesized derivatives have been investigated for their expected antibacterial activities against Gram-positive bacteria (Staphylococcus aureus CMCC 26003) and Gram-negative bacteria (Escherichia coli CMCC 44102). Among these compounds, only 4c (MIC = 12.5 µg/ml) and 4d (MIC = 25 µg/ml) exhibited antibacterial activity comparable to sanjuanolide (MIC = 12.5 µg/ml, against S. aureus CMCC 26003), and the results of subsequent in vivo experiments on sanjuanolide suggest that sanjuanolide exhibits bacteriostatic and bactericidal effects by altering the cellular structure, disrupting the integrity of cell membranes, and reducing the outer membrane potential.

Electron Transfer Strategies to Regulate Carriers' Separation for Intensive Pyroelectric Dynamic Therapy With Simultaneous Photothermal Therapy.

Endogenic heat shock proteins and uneven local heat distribution are two main problems in traditional tumor hyperthermia therapy strategies. Aiming at solving these problems, we designed Au-SnSe-PVP nanomaterials (ASNPs) by modifying Au nanoparticles (Au-NPs) and biocompatible PVP on SnSe nanorods via a new reactive oxygen species production strategy. The ASNPs with excellent photothermal conversion performance can produce thermoelectric effects in response to temperature differences during photothermal conversion. The modification of Au-NPs can attract free electron (e-) to accumulate and promote the separation of e- and holes (h+) in the thermoelectric process, thereby further promoting e--rich Au-NPs-induced H2O2 homolysis and h+-H2O half-reaction to generate hydroxyl radicals, realizing the synergistic application of photothermal therapy and pyroelectric dynamic therapy in tumor treatment.

Constructing Electron Levers in Perovskite Nanocrystals to Regulate the Local Electron Density for Intensive Chemodynamic Therapy.

The local electron density of an atom is one key factor that determines its chemical properties. Regulating electron density can promote the atom's reactivity and so reduce the reaction activation energy, which is highly desired in many chemical applications. Herein, we report an intra-crystalline electron lever strategy, which can regulate the electron density of reaction centre atoms via manipulating ambient lattice states, for Fenton activity improvement. Typically, with the assistance of ultrasound, the Mn4+ -O-Fe3+ bond in BiFe0.97 Mn0.03 O3 perovskite nanocrystals can drive valence electrons and free electrons to accumulate on Fe atoms by a polarization electric field originated from the designed lattice strain. The increase of electron density significantly improves the catalytic activity of Fe, decreasing the activation energy of BiFe0.97 Mn0.03 O3 -mediated Fenton reaction by 52.55 %, and increasing the . OH yield by 9.21-fold. This study provides a new way to understand the sono-Fenton chemistry, and the increased . OH production enables a highly effective chemodynamic therapy.

Structure-Activity Relationship Study of Rakicidins: Overcoming Chronic Myeloid Leukemia Resistance to Imatinib with 4-Methylester-Rakicidin A.

Natural product rakicidin A induces cell death in TKI-resistant chronic myelogenous leukemia (CML) cells. Therefore, 14 rakicidin A analogues were synthesized via a highly efficient combinatorial strategy and were evaluated against CML cell lines. The conjugated diene moiety was found to be crucial for the anti-CML activity of rakicidin A, and the changes in the configuration(s) at C-2, C-3, C-14, C-15, and C-16 resulted in lower levels of anti-CML activity. The most promising compound was 4-methylester rakicidin A (1a). Compared with rakicidin A, 1a exhibited 2.8-fold greater potency against the imatinib-resistant cell line K562/G(+) and approximately 100-fold enhanced potency compared with that of imatinib. Furthermore, compound 1a demonstrated a significantly lower resistance index against Ba/F3 cells expressing BCR-ABL(T315I) than bosutinib, dasatinib, nilotinib, and ponatinib, while 1a exhibited less effect on normal hematopoietic cells. Preliminary results indicated that 1a down-regulated caspase-3 and PARP, which contributes to its K562 cell inhibitory activity.

Total synthesis and determination of the absolute configuration of rakicidin A.

Rakicidin A is a cyclic depsipeptide that has exhibited unique growth inhibitory activity against chronic myelogenous leukemia stem cells. Furthermore, rakicidin A has five chiral centers with unknown stereochemical assignment, and thus, can be represented by one of 32 possible stereoisomers. To predict the most probable stereochemistry of rakicidin A, calculations and structural comparison with natural cyclic depsipeptides were applied. A total synthesis of the proposed structure was subsequently completed and highlighted by the creation of a sterically hindered ester bond (C1-C15) through trans-acylation from an easily established isomer (C1-C13). The analytic data of the synthetic target were consistent with that of natural rakicidin A, and then the absolute configuration of rakicidin A was assigned as 2S, 3S, 14S, 15S, 16R. This work suggests strategies for the determination of unknown chiral centers in other cyclic depsipeptides, such as rakicidin B, C, D, BE-43547, and vinylamycin, and facilitates the investigations of rakicidin A as an anticancer stem cell agent.