Discovery of novel amide derivatives against VEGFR-2/tubulin with potent antitumor and antiangiogenic activity.

Dual-target agents have more advantages than drug combinations for cancer treatment. Here, we designed and synthesized a series of novel VEGFR-2/tubulin dual-target inhibitors through a molecular hybridization strategy, and the activities of all the synthesized compounds were tested against tubulin and VEGFR-2. Among which, compound 19 exhibited strong potency against tubulin and VEGFR-2, with IC50 values of 0.76 ± 0.11 µM and 15.33 ± 2.12 nM, respectively. Additionally, compound 19 not only had significant antiproliferative effects on a series of human cancer cell lines, especially MGC-803 cells (IC50 = 0.005 ± 0.001 µM) but also overcame drug resistance in Taxol-resistant MGC-803 cells, with an RI of 1.8. Further studies showed that compound 19 could induce tumor cell apoptosis by reducing the mitochondrial membrane potential, increasing the level of ROS, facilitating the induction of G2/M phase arrest, and inhibiting the migration and invasion of tumor cells in a dose-dependent manner. In addition, compound 19 also exhibits potent antiangiogenic effects by blocking the VEGFR-2/PI3K/AKT pathway and inhibiting the tubule formation, invasion, and migration of HUVECs. More importantly, compound 19 demonstrated favorable pharmacokinetic profiles, robust in vivo antitumor efficacy, and satisfactory safety profiles. Overall, compound 19 can be used as a lead compound for the development of tubulin/VEGFR-2 dual-target inhibitors.

[Chemical constituents from Cinnamomi Ramulus decoction].

Six compounds were isolated from the ethyl acetate extracts of Cinnamomi Ramulus decoction by RP-18, silica gel, Sephadex LH-20 column chromatography, together with prep-HPLC methods. Based on HR-ESI-MS, MS, 1D and 2D NMR spectral analyses, the structures of the six compounds were identified as 4,5,10,11-tetrahydroxybisabol-7-ene(1), 4,5,10,11-tetrahydroxybisabolin(2), 1-phenyl-1,2,3-glycerol(3),(+)-lyoniresinol(4), benzoic acid(5), and decumbic acid(6). Compound 1 was a new bisabolene-type sesquiterpene, and compounds 2 and 3 were isolated from the Cinnamomi Ramulus for the first time. Moreover, the bisabolene-type sesquiterpene(2) was assayed for its anti-inflammatory activity and cytotoxicity to human pancreatic cancer cells(PANC-1 cells). RESULTS:: showed that compound 2 exhibited an inhibitory rate of 32.9% on nitric oxide(NO) at a dose of 40 µmol·L~(-1) and a proliferation inhibition rate of 14.5% against PANC-1 cells at a dose of 20 µmol·L~(-1). It did not demonstrate significant activity.

Low-Temperature Cross-Linked Hole Transport Layer for High-Performance Blue Quantum-Dot Light-Emitting Diodes.

Quantum-dot light-emitting diodes (QLEDs), a kind of promising optoelectronic device, demonstrate potential superiority in next-generation display technology. Thermal cross-linked hole transport materials (HTMs) have been employed in solution-processed QLEDs due to their excellent thermal stability and solvent resistance, whereas the unbalanced charge injection and high cross-linking temperature of cross-linked HTMs can inhibit the efficiency of QLEDs and limit their application. Herein, a low-temperature cross-linked HTM of 4,4'-bis(3-(((4-vinylbenzyl)oxy)methyl)-9H-carbazol-9-yl)-1,1'-biphenyl (DV-CBP) with a flexible styrene side chain is introduced, which reduces the cross-linking temperature to 150 °C and enhances the hole mobility up to 1.01 × 10-3 cm2 V-1 s-1. More importantly, the maximum external quantum efficiency of 21.35% is successfully obtained on the basis of the DV-CBP as a cross-linked hole transport layer (HTL) for blue QLEDs. The low-temperature cross-linked high-mobility HTL using flexible side chains could be an excellent alternative for future HTL development.

A comprehensive review of natural product-derived compounds acting on P2X7R: The promising therapeutic drugs in disorders.

BACKGROUND: The P2X7 receptor (P2X7R) is known to play a significant role in regulating various pathological processes associated with immune regulation, neuroprotection, and inflammatory responses. It has emerged as a potential target for the treatment of diseases. In addition to chemically synthesized small molecule compounds, natural products have gained attention as an important source for discovering compounds that act on the P2X7R. PURPOSE: To explore the research progress made in the field of natural product-derived compounds that act on the P2X7R. METHODS: The methods employed in this review involved conducting a thorough search of databases, include PubMed, Web of Science and WIKTROP, to identify studies on natural product-derived compounds that interact with P2X7R. The selected studies were then analyzed to categorize the compounds based on their action on the receptor and to evaluate their therapeutic applications, chemical properties, and pharmacological actions. RESULTS: The natural product-derived compounds acting on P2X7R can be classified into three categories: P2X7R antagonists, compounds inhibiting P2X7R expression, and compounds regulating the signaling pathway associated with P2X7R. Moreover, highlight the therapeutic applications, chemical properties and pharmacological actions of these compounds, and indicate areas that require further in-depth study. Finally, discuss the challenges of the natural products-derived compounds exploration, although utilizing compounds from natural products for new drug research offers unique advantages, problems related to solubility, content, and extraction processes still exist. CONCLUSION: The detailed information in this review will facilitate further development of P2X7R antagonists and potential therapeutic strategies for P2X7R-associated disorders.

RNA-binding protein RBM5 plays an essential role in acute myeloid leukemia by activating the oncogenic protein HOXA9.

BACKGROUND: The oncogenic protein HOXA9 plays a critical role in leukemia transformation and maintenance, and its aberrant expression is a hallmark of most aggressive acute leukemia. Although inhibiting the upstream regulators of HOXA9 has been proven as a significant therapeutic intervention, the comprehensive regulation network controlling HOXA9 expression in leukemia has not been systematically investigated. RESULTS: Here, we perform genome-wide CRISPR/Cas9 screening in the HOXA9-driven reporter acute leukemia cells. We identify a poorly characterized RNA-binding protein, RBM5, as the top candidate gene required to maintain leukemia cell fitness. RBM5 is highly overexpressed in acute myeloid leukemia (AML) patients compared to healthy individuals. RBM5 loss triggered by CRISPR knockout and shRNA knockdown significantly impairs leukemia maintenance in vitro and in vivo. Through domain CRISPR screening, we reveal that RBM5 functions through a noncanonical transcriptional regulation circuitry rather than RNA splicing, such an effect depending on DNA-binding domains. By integrative analysis and functional assays, we identify HOXA9 as the downstream target of RBM5. Ectopic expression of HOXA9 rescues impaired leukemia cell proliferation upon RBM5 loss. Importantly, acute protein degradation of RBM5 through auxin-inducible degron system immediately reduces HOXA9 transcription. CONCLUSIONS: We identify RBM5 as a new upstream regulator of HOXA9 and reveal its essential role in controlling the survival of AML. These functional and molecular mechanisms further support RBM5 as a promising therapeutic target for myeloid leukemia treatment.

Systematic characterization of the HOXA9 downstream targets in MLL-r leukemia by noncoding CRISPR screens.

Accumulating evidence indicates that HOXA9 dysregulation is necessary and sufficient for leukemic transformation and maintenance. However, it remains largely unknown how HOXA9, as a homeobox transcriptional factor, binds to noncoding regulatory sequences and controls the downstream genes. Here, we conduct dropout CRISPR screens against 229 HOXA9-bound peaks identified by ChIP-seq. Integrative data analysis identifies reproducible noncoding hits, including those located in the distal enhancer of FLT3 and intron of CDK6. The Cas9-editing and dCas9-KRAB silencing of the HOXA9-bound sites significantly reduce corresponding gene transcription and impair cell proliferation in vitro, and in vivo by transplantation into NSG female mice. In addition, RNA-seq, Q-PCR analysis, chromatin accessibility change, and chromatin conformation evaluation uncover the noncoding regulation mechanism of HOXA9 and its functional downstream genes. In summary, our work improves our understanding of how HOXA9-associated transcription programs reconstruct the regulatory network specifying MLL-r dependency.

Fluorescence probe for real-time malonaldehyde detection in epilepsy model.

Oxidative stress, a condition involving an imbalance between reactive oxygen species (ROS) and antioxidants, is closely linked to epilepsy, contributing to abnormal neuronal excitability. This study introduces a novel fluorescent probe, the MDP probe, designed for the efficient detection of malondialdehyde (MDA), a critical biomarker associated with oxidative stress. The MDP probe offers several key advantages, including high sensitivity with a low detection limit of 0.08 µM for MDA, excellent selectivity for MDA even in the presence of interfering substances, and biocompatibility, making it suitable for cell-based experiments. The probe allows for real-time monitoring of MDA levels, enabling dynamic studies of oxidative stress. In vivo experiments in mice demonstrate its potential for monitoring MDA levels, particularly in epilepsy models, which could have implications for disease research and diagnosis. Overall, the MDP probe represents a promising tool for studying oxidative stress, offering sensitivity and specificity in cellular and in vivo settings. Its development opens new avenues for exploring the role of oxidative stress in various biological processes and diseases, contributing to advancements in healthcare and biomedical research.

Discovery of N-(2-oxoethyl) sulfanilamide-derived inhibitors of KAT6A (MOZ) against leukemia by an isostere strategy.

KAT6A has been identified as a new target for leukemia treatment. The histone acetyltransferase activity of KAT6A is essential for normal hematopoietic stem cell self-renewal, and mutations or translocations are regarded as one of the major causes of leukemia development. In previous studies, CTX-0124143 has been shown to be a class of KAT6A inhibitors with a sulfonyl hydrazide backbone. However, weak activity, poor selectivity and pharmacokinetic problems have hindered its clinical application. In this work, the N‒N bond in compound CTX-0124143 was replaced by an N-C bond, and the aromatic rings were replaced on both sides. Finally, we obtained Compound 6j. Compared to CTX-0124143, 6j showed a 16-fold stronger inhibition of KAT6A (0.49 µM vs. 0.03 µM) with high selectivity. In addition, 6j exhibited strong antitumor activity on four leukemia cell lines. Moreover, 6j showed significant improvement in metabolic stability and pharmacokinetics in vivo and in vitro. In conclusion, 6j shows excellent potential as a promising anti-leukemia drug candidate.

Angiogenic signaling pathways and anti-angiogenic therapy for cancer.

Angiogenesis, the formation of new blood vessels, is a complex and dynamic process regulated by various pro- and anti-angiogenic molecules, which plays a crucial role in tumor growth, invasion, and metastasis. With the advances in molecular and cellular biology, various biomolecules such as growth factors, chemokines, and adhesion factors involved in tumor angiogenesis has gradually been elucidated. Targeted therapeutic research based on these molecules has driven anti-angiogenic treatment to become a promising strategy in anti-tumor therapy. The most widely used anti-angiogenic agents include monoclonal antibodies and tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) pathway. However, the clinical benefit of this modality has still been limited due to several defects such as adverse events, acquired drug resistance, tumor recurrence, and lack of validated biomarkers, which impel further research on mechanisms of tumor angiogenesis, the development of multiple drugs and the combination therapy to figure out how to improve the therapeutic efficacy. Here, we broadly summarize various signaling pathways in tumor angiogenesis and discuss the development and current challenges of anti-angiogenic therapy. We also propose several new promising approaches to improve anti-angiogenic efficacy and provide a perspective for the development and research of anti-angiogenic therapy.

BET inhibitors: an updated patent review (2018-2021).

INTRODUCTION: Bromodomain and extraterminal (BET) proteins are epigenetic readers that regulate gene transcription and cell growth by binding to acetylated lysine residues on histones. They are involved in many physiological processes and pathological conditions, such as cancer, inflammation, and metabolic diseases. Blockade of BET proteins has become an encouraging approach for the treatment of these human diseases, especially cancer. To date, a number of potent and specific BET inhibitors have been discovered and many of them have entered clinical trials. AREAS COVERED: This review aims at providing an overview of molecular mechanisms of BET inhibitors and highlighting the research advancements published in recent patent literatures between 2018 and 2021. Web of Science, PubMed, SciFinder, WIPO, EPO, USPTO and CNIPA databases were used for searching the literature and patents for BET inhibitors. EXPERT OPINION: In recent years, an increasing number of structurally diverse BET inhibitors have been identified, including pan BET inhibitors, BD1 or BD2 selective BET inhibitors, bivalent BET inhibitors, kinase and BET dual inhibitors, and BET-PROTACs. Despite many challenges, BET inhibitors have high potential in the treatment of cancer and other diseases, and the development of next-generation BET inhibitors could be promising.

Loss of Lipocalin 10 Exacerbates Diabetes-Induced Cardiomyopathy via Disruption of Nr4a1-Mediated Anti-Inflammatory Response in Macrophages.

Metabolic disorders (i.e., hyperglycemia, hyperlipidemia, and hyperinsulinemia) cause increased secretion of inflammatory cytokines/chemokines, leading to gradual loss of cardiac resident macrophage population and increased accumulation of inflammatory monocytes/macrophages in the heart. Such self-perpetuating effect may contribute to the development of cardiomyopathy during diabetes. Recent meta-analysis data reveal that lipocalin 10 (Lcn10) is significantly downregulated in cardiac tissue of patients with heart failure but is increased in the blood of septic patients. However, the functional role of Lcn10 in cardiac inflammation triggered by metabolic disorders has never been investigated. In this study, we demonstrate that the expression of Lcn10 in macrophages was significantly decreased under multiple metabolic stress conditions. Furthermore, Lcn10-null macrophages exhibited pro-inflammatory phenotype in response to inflammation stimuli. Next, using a global Lcn10-knockout (KO) mouse model to induce type-2 diabetes (T2D), we observed that loss of Lcn10 promoted more pro-inflammatory macrophage infiltration into the heart, compared to controls, leading to aggravated insulin resistance and impaired cardiac function. Similarly, adoptive transfer of Lcn10-KO bone marrow cells into X-ray irradiated mice displayed higher ratio of pro-/anti-inflammatory macrophages in the heart and worsened cardiac function than those mice received wild-type (WT) bone marrows upon T2D conditions. Mechanistically, RNA-sequencing analysis showed that Nr4a1, a nuclear receptor known to have potent anti-inflammatory effects, is involved in Lcn10-mediated macrophage activation. Indeed, we found that nuclear translocation of Nr4a1 was disrupted in Lcn10-KO macrophages upon stimulation with LPS + IFNγ. Accordingly, treatment with Cytosporone B (CsnB), an agonist of Nr4a1, attenuated the pro-inflammatory response in Lcn10-null macrophages and partially improved cardiac function in Lcn10-KO diabetic mice. Together, these findings indicate that loss of Lcn10 skews macrophage polarization to pro-inflammatory phenotype and aggravates cardiac dysfunction during type-2 diabetes through the disruption of Nr4a1-mediated anti-inflammatory signaling pathway in macrophages. Therefore, reduction of Lcn10 expression observed in diabetic macrophages may be responsible for the pathogenesis of diabetes-induced cardiac dysfunction. It suggests that Lcn10 might be a potential therapeutic factor for diabetic heart failure.

Improved ensemble of differential evolution variants.

In the field of Differential Evolution (DE), a number of measures have been used to enhance algorithm. However, most of the measures need revision for fitting ensemble of different combinations of DE operators-ensemble DE algorithm. Meanwhile, although ensemble DE algorithm may show better performance than each of its constituent algorithms, there still exists the possibility of further improvement on performance with the help of revised measures. In this paper, we manage to implement measures into Ensemble of Differential Evolution Variants (EDEV). Firstly, we extend the collecting range of optional external archive of JADE-one of the constituent algorithm in EDEV. Then, we revise and implement the Event-Triggered Impulsive (ETI) control. Finally, Linear Population Size Reduction (LPSR) is used by us. Then, we obtain Improved Ensemble of Differential Evolution Variants (IEDEV). In our experiments, good performers in the CEC competitions on real parameter single objective optimization among population-based metaheuristics, state-of-the-art DE algorithms, or up-to-date DE algorithms are involved. Experiments show that our IEDEV is very competitive.

Psidguajones A and B, a pair of complex meroterpenoid epimers from the leaves of Psidium guajava.

Psidguajones A and B, a pair of dimeric sesquiterpene-based meroterpenoid epimers, have been isolated from the leaves of Psidium guajava for the first time. Their structures were confirmed by comprehensive spectroscopic techniques combined with a comparison of experimental and calculated ECD data.

A hybrid double-density dual-tree discrete wavelet transformation and marginal Fisher analysis for scoring sleep stages from unprocessed single-channel electroencephalogram.

BACKGROUND: We demonstrate an innovative approach of automated sleep recording formed on the electroencephalogram (EEG) with one channel. METHODS: In this study, double-density dual-tree discrete wavelet transformation (DDDTDWT) was used for decomposing the image, and marginal Fisher analysis (MFA) was used for reducing the dimension. A proposed model on unprocessed EEG models was used on monitored training of 5-group sleep phase forecasting. RESULTS: Our network includes a 14-row structure, and a 30-s period was extracted as input in order to be categorized which is followed by second and third period prior to the first 30-s period. Another consecutive period for temporal tissue was added which is not required to a signal preprocess and attribute data derivation phase. Our means of evaluating and improving our approach was to use input from the Sleep Heart Health Study (SHHS), which is a large study field aimed at using research from numerous centers and people and which studies the records of specialist-rated polysomnography (PSG). Performance measures could reach the desired level, which is a precision of 0.87 and a Cohen's kappa of 0.81. CONCLUSIONS: The use of a large, collaborative study of specialist graders can enhance the likelihood of good globalization. Overall, the novel approach learned by our network showcases the models based on each category.

GDF3 Protects Mice against Sepsis-Induced Cardiac Dysfunction and Mortality by Suppression of Macrophage Pro-Inflammatory Phenotype.

Macrophages are critical for regulation of inflammatory response during endotoxemia and septic shock. However, the mediators underlying their regulatory function remain obscure. Growth differentiation factor 3 (GDF3), a member of transforming growth factor beta (TGF-ß) superfamily, has been implicated in inflammatory response. Nonetheless, the role of GDF3 in macrophage-regulated endotoxemia/sepsis is unknown. Here, we show that serum GDF3 levels in septic patients are elevated and strongly correlate with severity of sepsis and 28-day mortality. Interestingly, macrophages treated with recombinant GDF3 protein (rGDF3) exhibit greatly reduced production of pro-inflammatory cytokines, comparing to controls upon endotoxin challenge. Moreover, acute administration of rGDF3 to endotoxin-treated mice suppresses macrophage infiltration to the heart, attenuates systemic and cardiac inflammation with less pro-inflammatory macrophages (M1) and more anti-inflammatory macrophages (M2), as well as prolongs mouse survival. Mechanistically, GDF3 is able to activate Smad2/Smad3 phosphorylation, and consequently inhibits the expression of nod-like receptor protein-3 (NLRP3) in macrophages. Accordingly, blockade of Smad2/Smad3 phosphorylation with SB431542 significantly offsets rGDF3-mediated anti-inflammatory effects. Taken together, this study uncovers that GDF3, as a novel sepsis-associated factor, may have a dual role in the pathophysiology of sepsis. Acute administration of rGDF3 into endotoxic shock mice could increase survival outcome and improve cardiac function through anti-inflammatory response by suppression of M1 macrophage phenotype. However, constitutive high levels of GDF3 in human sepsis patients are associated with lethality, suggesting that GDF3 may promote macrophage polarization toward M2 phenotype which could lead to immunosuppression.

Engineering pyrolysis biochar via single-step microwave steam activation for hazardous landfill leachate treatment.

Improving the sustainability and cost-effectiveness of biochar production is crucial to meet increased global market demand. Here, we developed a single-step microwave steam activation (STMSA) as a simplified yet efficient method to produce microwave activated biochar (MAB) from waste palm shell (WPS). The STMSA recorded a higher heating rate (70 °C/min) and higher conversion (45 wt%) of WPS into highly microporous MAB (micropore surface area of 679.22 m2/g) in contrast with the conventional heating approach (≤ 12-17 wt%). The MAB was then applied as biosorbent for hazardous landfill leachate (LL) treatment and the adsorption performance was compared with commercial activated carbon under different pH, adsorbent quantity, adsorbate concentrations, and contact times. The MAB demonstrated high adsorption capacity, achieving maximum adsorption efficiency at 595 mg/g and 65 % removal of chemical oxygen demand (COD) with 0.4 g/L of adsorbent amount under optimal acidic conditions (pH ≈ 2-3) after 24 h of contact time. The Freundlich isotherm and pseudo second-order kinetic models were well-fitted to explain the equilibrium adsorption and kinetics. The results indicate the viability of STMSA as a fast and efficient approach to produce activated biochar as a biosorbent for the treatment of hazardous landfill leachate.

Biomimetic Synthesis of Psiguajdianone Guided Discovery of the Meroterpenoids from Psidium guajava.

Psiguajdianone (1), a novel caryophyllene-derived meroterpenoid dimer, was isolated from Psidium guajava. The structure of 1 was determined by X-ray analysis and confirmed by total synthesis. Our synthetic strategy involves biomimetic cascade Knoevenagel condensation/hetero-Diels-Alder reaction and dimerization. Notably, the caryophyllene-derived meroterpenoids obtained during our synthesis were first identified as artifacts in the laboratory, and five of them were proven to be natural products present in the plant. Moreover, these compounds show significant anti-inflammatory activity.

Microwave pyrolysis valorization of used baby diaper.

Used baby diaper consists of a combination of decomposable cellulose, non-biodegradable plastic materials (e.g. polyolefins) and super-absorbent polymer materials, thus making it difficult to be sorted and separated for recycling. Microwave pyrolysis was examined for its potential as an approach to transform used baby diapers into value-added products. Influence of the key operating parameters comprising process temperature and microwave power were investigated. The pyrolysis showed a rapid heating process (up to 43 °C/min of heating rate) and quick reaction time (20-40 min) in valorizing the used diapers to generate pyrolysis products comprising up to 43 wt% production of liquid oil, 29 wt% gases and 28 wt% char product. Microwave power and operating temperature were observed to have impacts on the heating rate, process time, production and characteristics of the liquid oil and solid char. The liquid oil contained alkanes, alkenes and esters that can potentially be used as chemical additives, cosmetic products and fuel. The solid char contained high carbon, low nitrogen and free of sulphur, thus showing potential for use as adsorbents and soil additives. These observations demonstrate that microwave pyrolysis has great prospect in transforming used baby diaper into liquid oil and char products that can be utilised in several applications.

Design, preparation and evaluation of a high performance sensor for formaldehyde based on a novel hybride nonocomposite ZnWO3/rGO.

The ultrasound wave assisted synthesis of a novel ZnWO3/rGO hybrid nono composition (ZnWO3/rGO HNC) as a high performance sensor for formaldehyde (FA) has been reported. Different techniques of analysis such as XRD, FE-SEM, TGA, XPS, HRTEM and BET were applied for morphological and spectroscopic characterization of the ZnWO3/rGO HNC. The sensing evaluation of the constructed sensor showed high selectivity, sensitivity and a linear correlation between achieved responses and concentration of target gas (1-10 ppm) with R2 = 0.993 at temperature of 95 °C. The determination of FA was validated and performed using gas chromatography-mass spectrometry combined by solid phase micro-extraction after derivatization with O-(2,3,4,5,6-pentafluoro-benzyl)-hydroxylamine hydrochloride. Validation was carried out in terms of limit of detection linearity, precision, and recovery. The mechanistic evaluation of sensing behavior of the ZnWO3/rGO HNC was interpreted based on large specific surface area (SSA) to volume, mesoporous structure and the heterojunction between rGO and ZnWO3 at the interface between the rGO and ZnWO3.

Antioxidant and xanthine oxidase inhibitory activities of total polyphenols from onion.

Onions (Allium cepa L.) comprise a valuable vegetable crop in many countries. Modern scientific research has shown that onions possess many biological activities, including antibacterial, anticancer, hypoglycemic, hypolipidemic, antiplatelet aggregation, and antioxidant activities. The goal of this study was to investigate the impact of total onion polyphenols on antioxidant and xanthine oxidase (XO) inhibitory activities. Total onion polyphenols showed significant antioxidant activity in DPPH, FRAP, and OH-assays (IC50 [µg/mL]), 43.24, 560.61, and 12.97, respectively). In a X/XO system, antioxidant properties of these polyphenols significantly inhibited XO activity (IC50 [µg/mL], 17.36). These results indicated that total onion polyphenols showed promising antioxidant and anti-gout properties and might be used as potential, natural drugs against oxidative diseases after successful studies in vivo as well as clinical trials.