Design, synthesis, and biological evaluation of novel tryptanthrin derivatives as selective acetylcholinesterase inhibitors for the treatment of Alzheimer's disease.

Two novel series of tryptanthrin (TRYP) derivatives were designed and synthesized as multifunctional agents for the treatment of Alzheimer's disease (AD). Inhibition assay against cholinesterase (ChE) indicated that these derivatives can act as acetylcholinesterase (AChE) inhibitors with selectivity over butyrylcholinesterase (BuChE). Among them, n1 exhibited the most excellent ChE inhibitory potency (AChE, IC50 = 12.17 ± 1.50 nM; BuChE, IC50 = 6.29 ± 0.48 µΜ; selectivity index = 517). Molecular docking studies indicated that compound n1 can interact with amino acid residues in the catalytic active site and peripheral anionic site of AChE and the molecular dynamics (MD) simulation studies demonstrated that the AChE-n1 complex had good stability. N1 also exhibited anti-amyloid-ß (Aß) aggregation (63.48 % ± 1.02 %, 100 µΜ) and anti-neuroinflammation activity (NO, IL-1ß, TNF-α; IC50 = 2.13 ± 0.54 µΜ, 2.21 ± 0.37 µΜ, 2.47 ± 0.07 µΜ, respectively), and n1 had neuroprotective and metal-chelating properties. Further studies indicated n1 had proper blood-brain barrier permeability in the Parallel artificial membrane permeation assay. In vivo studies found that n1 effectively improved learning and memory impairment in scopolamine-induced AD mouse models. Nissl staining ofmice hippocampaltissue sections revealed that n1 restored neuronal cells in the hippocampus CA3 and CA1 regions. These findings suggested that n1 can be a promising compound for further development of multifunctional agents for AD treatment.

Discovery of novel TLR4/MD-2 inhibitors: Receptor structure-based virtual screening studies and anti-inflammatory evaluation.

In this study, a receptor structure-based virtual screening strategy was constructed using a computer-aided drug design. First, the compounds were filtered based on the Lipinski pentad and adsorption, distribution, metabolism, excretion, and toxicity profiles. Then, receptor structure-based pharmacophore models were constructed and screened. Finally, the in vitro toxicity and anti-inflammatory activities of hit compounds were initially evaluated to investigate their in vitro anti-inflammatory effects and mechanisms of action. The results revealed that hit 94 had the best anti-inflammatory activity and low toxicity while inhibiting the activation of Toll-like receptor (TLR) 4/myeloid differentiation factor 2 (MD2)-associated signaling pathways of nuclear factor-κB and mitogen-activated protein kinase. In vivo adjuvant arthritis results also revealed that hit 94 ameliorated foot swelling to a greater extent in rats compared with the positive control drug indomethacin. These results suggest that hit 94 can be used as a potential TLR/MD2 inhibitor for inflammatory diseases.

Protective effects of (4-(1,2,4-oxadiazol-5-yl)phenyl)-2-aminoacetamide derivatives to adjuvant-induced arthritis rats by regulating the NF-κB signaling pathway.

A series of (4-(1,2,4-oxadiazol-5-yl) phenyl)-2-aminoacetamide derivatives showed good anti-neuroinflammation in our previous study. Some studies have proven that the anti-inflammatory compounds effective for some specific diseases could also be used to treat other inflammatory diseases. In this study, the effects of these compounds on arthritis were further analyzed. First, in-vitro anti-inflammatory activity assessment indicated that these compounds have good anti-inflammatory activity. Among them, compound f15 showed the most prominent performance, it could significantly inhibit the production of relevant inflammatory factors in lipopolysaccharide (LPS)-induced RAW264.7 cells, with IC50 values of 1.55 ± 0.33, 3.83 ± 0.19, and 7.03 ± 0.24 µM against NO, IL-1ß, and TNF-α production, respectively. Preliminary mechanism studies indicated that f15 blocked the excitation of nuclear factor κB (NF-кB) signaling pathway in a concentration-dependent manner. Furthermore, in-vivo experiment showed that f15 reduced secondary foot swelling and arthritic index in adjuvant-induced arthritis (AIA) rats and inhibited the production of TNF-α and IL-1ß in serum. Histopathological analysis revealed that f15 alleviated inflammatory cell infiltration and synovial hyperplasia in rats with AIA. Thus, compound f15 could be considered to have the potential to be developed as a treatment for arthritis.

Synthesis and evaluation of the anti-inflammatory activity of novel 8-quinolinesulfonamide derivatives as TLR4/MD-2 inhibitors with efficacy in adjuvant-induced arthritis.

In this study, a series of 8-quinolinesulfonamidederivatives was synthesized, and their anti-inflammatory activity was evaluated. Among them, compound 3l was found to be the best anti-inflammatory agent, with IC50 values of 2.61 ± 0.39, 9.74 ± 0.85, and 12.71 ± 1.34 µM against NO, TNF-α and IL-1ß production respectively. And 3l could significantly prevent lipopolysaccharide (LPS)-induced expression of inflammatory mediators (iNOS and COX-2). Molecule docking results showed that 3l could bind to the LPS binding site of toll-like receptor 4 (TLR4)/MD-2, and 3l was then identified as TLR4/MD-2 inhibitor by co-immunoprecipitation (co-IP) and cellular thermal shift assay (CTESA). Preliminary mechanism studies indicated that 3l could prevent TLR4 from being activated by disrupting TLR4/MD-2 heterodimerization and TLR4 homodimerization, thereby blocking the activation of the NF-κB/MAPK signaling pathway. Furthermore, observation of rat foot swelling, joint pathology and serum inflammatory cytokine levels proved that compound 3l had a significant therapeutic effect on adjuvant-induced arthritis (AIA) in rats in vivo. These results indicated that compound 3l is a potential anti-inflammatory agent, from which more effective anti-inflammatory drugs could be developed.

Discovery of novel deoxyvasicinone derivatives with benzenesulfonamide substituents as multifunctional agents against Alzheimer's disease.

A series of deoxyvasicinone derivatives with benzenesulfonamide substituents were designed and synthesized to find a multifunctional anti-Alzheimer's disease (AD) drug. The results of the biological activity evaluation indicated that most compounds demonstrated selective inhibition of acetylcholinesterase (AChE). Among them, g17 exhibited the most potent inhibitory effect on AChE (IC50 = 0.24 ± 0.04 µM). Additionally, g17 exhibited promising properties as a metal chelator and inhibitor of amyloid ß peptides self-aggregation (68.34 % ± 1.16 %). Research on oxidative stress has shown that g17 displays neuroprotective effects and effectively suppresses the intracellular accumulation of reactive oxygen species. Besides, g17 demonstrated remarkable anti-neuroinflammatory effects by significantly reducing the production of pro-inflammatory cytokines (such as NO, IL-1ß, and TNF-α) and inhibiting the expression of inflammatory mediators iNOS and COX-2. In vivo studies showed that g17 significantly improved AD model mice's cognitive and memory abilities. Histological examination of mouse hippocampal tissue sections using hematoxylin and eosin staining revealed that g17 effectively mitigates neuronal damage. Considering the multifunctional properties of g17, it is regarded as a promising lead compound for treating AD.

Experimental and Simulation Research on Femtosecond Laser Induced Controllable Morphology of Monocrystalline SiC.

Silicon carbide (SiC) is utilized in the automotive, semiconductor, and aerospace industries because of its desirable characteristics. Nevertheless, the traditional machining method induces surface microcracks, low geometrical precision, and severe tool wear due to the intrinsic high brittleness and hardness of SiC. Femtosecond laser processing as a high-precision machining method offers a new approach to SiC processing. However, during the process of femtosecond laser ablation, temperature redistribution and changes in geometrical morphology features are caused by alterations in carrier density. Therefore, the current study presented a multi-physics model that took carrier density alterations into account to more accurately predict the geometrical morphology for femtosecond laser ablating SiC. The transient nonlinear evolutions of the optical and physical characteristics of SiC irradiated by femtosecond laser were analyzed and the influence of laser parameters on the ablation morphology was studied. The femtosecond laser ablation experiments were performed, and the ablated surfaces were subsequently analyzed. The experimental results demonstrate that the proposed model can effectively predict the geometrical morphology. The predicted error of the ablation diameter is within the range from 0.15% to 7.44%. The predicted error of the ablation depth is within the range from 1.72% to 6.94%. This work can offer a new way to control the desired geometrical morphology of SiC in the automotive, semiconductor, and aerospace industries.

Discovery of Novel Tryptanthrin Derivatives with Benzenesulfonamide Substituents as Multi-Target-Directed Ligands for the Treatment of Alzheimer's Disease.

Based on the multi-target-directed ligands (MTDLs) approach, two series of tryptanthrin derivatives with benzenesulfonamide substituents were evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro biological assays indicated most of the derivatives had good cholinesterase inhibitory activity and neuroprotective properties. Among them, the target compound 4h was considered as a mixed reversible dual inhibitor of acetylcholinesterase (AChE, IC50 = 0.13 ± 0.04 µM) and butyrylcholinesterase (BuChE, IC50 = 6.11 ± 0.15 µM). And it could also potentially prevent the generation of amyloid plaques by inhibiting self-induced Aß aggregation (63.16 ± 2.33%). Molecular docking studies were used to explore the interactions of AChE, BuChE, and Aß. Furthermore, possessing significant anti-neuroinflammatory potency (NO, IL-1ß, TNF-α; IC50 = 0.62 ± 0.07 µM, 1.78 ± 0.21 µM, 1.31 ± 0.28 µM, respectively) reduced ROS production, and chelated biometals were also found in compound 4h. Further studies showed that 4h had proper blood-brain barrier (BBB) permeability and suitable in vitro metabolic stability. In in vivo study, 4h effectively ameliorated the learning and memory impairment of the scopolamine-induced AD mice model. These findings suggested that 4h may be a promising compound for further development as a multifunctional agent for the treatment of AD.

Novel tryptanthrin derivatives with benzenesulfonamide substituents: Design, synthesis, and anti-inflammatory evaluation.

Herein, two series of tryptanthrin derivatives with benzenesulfonamide substituents were designed and synthesized to discover novel anti-inflammatory agents. The anti-inflammatory activities of all derivatives were screened by evaluating their inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells. Among them, compound 8j exhibited the best NO inhibitory activity (IC50 = 1.25 ± 0.21 µM), with no obvious toxicity. Further evaluation showed that 8j could also significantly reduce the levels of pro-inflammatory cytokines interleukin-1ß (IL-1ß, IC50 = 8.48 ± 0.23 µM) and tumor necrosis factor-α (TNF-α, IC50 = 11.53 ± 0.35 µM) and downregulate the LPS-induced expression of iNOS and COX-2. Reverse docking of 8j suggested p38α as the molecular target, which is a well-known crucial player in the p38 MAPK signaling pathway that controls the transcription of pro-inflammatory mediators. Cellular thermal shift assay showed that 8j efficiently stabilized p38α in LPS-treated RAW264.7 cells. Western blot showed that inflammatory response was inhibited by 8j through inhibiting the phosphorylation of p38α and MK2 in the p38 MAPK signaling pathway. Finally, In vivo studies showed that 8j could significantly ameliorate the degree of foot swelling and knee joint pathology in adjuvant-induced arthritis (AIA) rats and reduce levels of TNF-α and IL-1ß in serum, achieving the effect of protecting synovial tissue and ameliorating arthritis. These findings suggested that 8j may be a promising compound for further development of anti-inflammatory agents.

CD73/NT5E-mediated ubiquitination of AURKA regulates alcohol-related liver fibrosis via modulating hepatic stellate cell senescence.

Alcohol-related liver disease (ALD) is the most common chronic liver disease worldwide; however, no effective treatment to prevent the progression of alcohol-related liver fibrosis (ALF) is available. CD73/NT5E, a nucleotidase, controls cellular homeostasis by combining extracellular purinergic signaling with intracellular kinase activity and gene transcription and is associated with cell proliferation, differentiation, and death. In this study, we demonstrated that CD73/NT5E had a more significant regulatory effect on the activation, proliferation, and apoptosis of HSCs compared with that of CD39/ENTPD1. We examined the expression of CD73/NT5E in the normal and fibrotic human livers. The absence of CD73/NT5E was protective in mouse models of ALF. In addition, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed that CD73/NT5E overexpression was related to the p53 signaling pathway, which regulates cell senescence. Proteins interacting with p53 were predicted using the STRING database. The overlap between proteomic analysis and STRING databases was for Aurora kinase A (AURKA), a cell cycle-regulated kinase. Coimmunoprecipitation (co-IP) assay and molecular docking confirmed that CD73/NT5E directly interacted with AURKA. We found that overexpression of CD73/NT5E inhibited AURKA ubiquitination, whereas p53 signaling was downregulated. Mechanistically, CD73/NT5E regulated ALF and the activation and senescence of stellate cells by binding to AURKA. These findings indicate that CD73/NT5E is a potential therapeutic target for ALF.

Fomesafen drift affects morphophysiology of sugar beet.

Fomesafen is an herbicide used in soybean production, and sugar beet is a sensitive crop to fomesafen. When the herbicide is sprayed in the field, it is easy to cause floating and depositing on non-target crops, resulting in crop poisoning and reducing yield. There are few on the phenomenon and mechanism of fomesafen herbicide drift on sugar beet. There are few reports on the phenomenon and mechanism of ether herbicide migration on phytotoxicity of sugar beet. Therefore, in this experiment, indoor potted plants were used to simulate the dose of fomesafen drift deposited on sugar beet in the field to study the effects of fomesafen on the growth, photosynthetic system, and physiological indexes of seedlings for sugar beet were studied. The results showed that fomesafen at the dose of 225 g a.i. ha-1 significantly inhibited the plant height, root length, and biomass of sugar beet. Compared with the control, the net photosynthetic rate, stoma conductance, transpiration rate, and total chlorophyll pigment content of leaves were reduced by 77.16%, 83.84%, 64.00%, and 28.13%, respectively. Treatment with a dose of 225 g a.i. ha-1 also damaged the photosynthetic system II of the leaves, lowering the performance index on absorption energy, maximum quantum yield and, the energy of electron transfer, causing photoinhibition and photodamage. In addition, fomesafen significantly increased the content of malondialdehyde and the activity of peroxidase in leaves of sugar beet, reducing the activities of superoxide dismutase and catalase. Overall, this study is helpful to understand the drift and deposition of fomesafen on sugar beet and to discuss the phytotoxicity risk and dose of fomesafen on the beet, as a result of controlling the dose of fomesafen sprayed in the field.

Design, synthesis, and biological evaluation of novel (4-(1,2,4-oxadiazol-5-yl)phenyl)-2-aminoacetamide derivatives as multifunctional agents for the treatment of Alzheimer's disease.

On the basis of our previous work, a novel series of (4-(1,2,4-oxadiazol-5-yl)phenyl)-2-aminoacetamide derivatives were synthesized and evaluated as multifunctional ligands for the treatment of Alzheimer's disease (AD). Biological evaluations indicated that the derivatives can be used as anti-AD drugs that have multifunctional properties, inhibit the activity of butyrylcholinesterase (BuChE), inhibit neuroinflammation, have neuroprotective properties, and inhibit the self-aggregation of Aß. Compound f9 showed good potency in BuChE inhibition (IC50: 1.28 ± 0.18 µM), anti-neuroinflammatory potency (NO, IL-1ß, TNF-α; IC50: 0.67 ± 0.14, 1.61 ± 0.21, 4.15 ± 0.44 µM, respectively), and inhibited of Aß self-aggregation (51.91 ± 3.90%). Preliminary anti-inflammatory mechanism studies indicated that the representative compound f9 blocked the activation of the NF-κB signaling pathway. Moreover, f9 exhibited 1,1-Diphenyl-2-picrylhydrazyl (DPPH) radical scavenging effect, and an inhibitory effect on the production of intracellular reactive oxygen species (ROS). In the bi-directional transport assay, f9 displayed proper blood-brain barrier (BBB) permeability. In addition, the title compound improved memory and cognitive functions in a mouse model induced by scopolamine. Hence, the compound f9 can be considered as a promising lead compound for further investigation in the treatment of AD.

Novel quinoline-based derivatives: A new class of PDE4B inhibitors for adjuvant-induced arthritis.

A total of 31 quinoline-based derivatives were designed and synthesized to develop novel anti-inflammatory drugs. After the toxicity of synthetic compounds to RAW264.7 cells were evaluated in vitro, their anti-inflammatory activity was assessed by inhibiting lipopolysaccharide (LPS)-induced NO production levels in the RAW264.7 cells. Among the derivatives, compound f4 had the best anti-inflammatory activity, which could reduce the production of pro-inflammatory cytokines NO, IL-1ß, and TNF-α with corresponding IC50 values of 20.40 ± 0.94, 18.98 ± 0.21 and 23.48 ± 0.46 µM. Western blot showed that f4 could inhibit the expression of LPS-induced inflammatory mediators iNOS and COX-2. Molecular docking showed that f4 could also enter the PDE4B receptor binding pocket, and the cellular thermal shift assay method indicated that the PDE4B protein bound to f4 had increased stability. Meanwhile, the inhibitory effect of this compound on the PDE4B enzyme (IC50 = 0.94 ± 0.36 µM) was comparable to that of the positive drug rolipram (IC50 = 1.04 ± 0.28 µM). Finally, in vivo studies showed that f4 could improve the degree of foot swelling and knee joint pathology in adjuvant-induced arthritic rats and decrease the levels of serum inflammatory factors TNF-α and IL-1ß in a dose-dependent manner. Therefore, the development and design of quinoline-based derivatives for anti-inflammatory applications could be considered opportunities and challenges.

Detection of organophosphorus pesticides: exploring oxime as a probe with improved sensitivity by CeO2-modified electrode.

In this paper, the catalytic activity of CeO2 NPs toward oxime oxidation was adopted for the first time to develop an electrochemical sensor with improved sensitivity toward the direct detection of organophosphorus pesticides (OPs) without electrochemical redox activity. To enhance the conductivity of the sensor, CeO2 NPs together with multi-walled carbon nanotubes (MWCNTs) were deposited onto a bare glassy carbon electrode (GCE) by the simple method of drop-casting. The electrochemical properties of the as-prepared sensor were evaluated in K3[Fe(CN)6] solution and the oxidation behavior of pralidoxime (PAM) chloride on the electrodes was characterized by cyclic voltammetry (CV) and differential pulse voltammetry (DPV). The results show that the modification of CeO2 onto the electrode not only increases the electroactive area of the electrode but also significantly increases the peak current of PAM chloride oxidation, which confirms that CeO2 has an electrocatalytic effect toward oxime oxidation. To evaluate the sensitivity of the as-fabricated sensor, the inhibition rate of PAM chloride peak current was tested in PAM chloride solution containing different concentrations of chlorpyrifos, which shows a very small detection limit of 2.5 × 10-9 M. In addition, the sensor successfully achieved a convenient and sensitive determination of OPs in vegetable extracts.

Prenatal and postnatal exposure risk assessment of chlorinated paraffins in mothers and neonates: Occurrence, congener profile, and transfer behavior.

Gestation and lactation are very sensitive and vulnerable stages for human growth and development. During these two periods, short-chain chlorinated paraffins (SCCPs) and medium-chain chlorinated paraffins (MCCPs) can be transported to neonates via transplacental and breastfeeding transfers, and eventually posing potential adverse effects to neonates. Up to date, no simultaneous investigation of prenatal and postnatal exposure of CPs is reported. To bridge this knowledge gap, we have analyzed SCCPs and MCCPs in 20 complete sets of maternal serum, umbilical cord serum, placenta, and breast milk. The levels of both ∑SCCP and ∑MCCP followed the order of maternal serum > breast milk > cord serum > placenta. The breastfeeding transfer ratios (RBM, ≈ 1.0) of CPs were greater than the corresponding transplacental transfer ratios (RCM, < 1.0), demonstrating the higher transport of CPs during the lactation period. The placental retention/or accumulation ratios (RPM) showed that CPs were effectively retained by the placental barrier. Furthermore, the total exposure amount of SCCPs and MCCPs during the lactation period was> 100 times higher than the gestation exposure amounts. This study helps to better understand the prenatal and postnatal exposure of CPs and provides a solid basis for accurate human health risk assessment of CPs.