Synthesis and anti-liver fibrosis activity of imidazole and thiazole compounds containing amino acids.

Four series of imidazoles (15a-g, 20c, and 20d) and thiazoles (18a-g, 22a, and 22b) possessing various amino acids were synthesized and evaluated for activin receptor-like kinase 5 (ALK5) inhibitory activities in an enzymatic assay. Among them, compounds 15g and 18c showed the highest inhibitory activity against ALK5, with IC50 values of 0.017 and 0.025 µM, respectively. Compounds 15g and 18c efficiently inhibited extracellular matrix (ECM) deposition in TGF-ß-induced hepatic stellate cells (HSCs), and eventually suppressed HSC activation. Moreover, compound 15g showed a good pharmacokinetic (PK) profile with a favorable half-life (t1/2 = 9.14 h). The results indicated that these compounds exhibited activity targeting ALK5 and may have potential in the treatment of liver fibrosis; thus they are worthy of further study.

Brazilin-7-acetate, a novel potential drug of Parkinson's disease, hinders the formation of α-synuclein fibril, mitigates cytotoxicity, and decreases oxidative stress.

Parkinson's disease (PD) is a prevalent neurodegenerative disorder characterized by the accumulation of α-synuclein (α-Syn) aggregates. However, there are currently no effective therapies for PD. Brazilin, an inhibitor of α-Syn aggregation, is unstable and toxic. Therefore, we have developed and synthesized derivatives of brazilin. One of these derivatives, called brazilin-7-acetate (B-7-A), has shown reduced toxicity and a stronger effect on inhibiting α-Syn aggregation. It showed that B-7-A prevented the formation of α-Syn fibers and disrupted existing fibers in a dosage-dependent manner. Additionally, B-7-A significantly reduced the cytotoxicity of α-Syn aggregates and alleviated oxidative stress in PC12 cells. The beneficial effects of B-7-A were also confirmed using the Caenorhabditis elegans model. These effects included preventing the accumulation of α-Syn clumps, improving behavior disorder, increasing lifespan, reducing oxidative stress, and protecting against lipid oxidation and loss. Finally, B-7-A showed good ADMET properties in silico. Based on these findings, B-7-A exhibits potential as a prospective treatment for PD.

Synthesis of and anti-fibrotic effect of pyrazole derivative J-1048: Inhibition of ALK5 as a novel approach to liver fibrosis targeting inflammation.

Liver fibrosis is a worldwide challenge of health issue. Developing effective new drugs for treating liver fibrosis is of great importance. In recent years, chemically synthesized drugs have significant advantages in treating liver fibrosis. Small molecule pyrazole derivatives as activin receptor-like kinase 5 (ALK5) inhibitors have also shown anti-fibrotic and tumor growth inhibitory effects. To develop the candidate with anti-fibrotic effect, we synthesized a novel pyrazole derivative, J-1048. The inhibitory effect of J-1048 on ALK5 and p38α mitogen-activated protein (MAP) kinase activity was assessed by enzymatic assays. We established an in vivo liver fibrosis model by injecting thioacetamide (TAA) into mice and in vitro model of TGF-ß stimulated hepatic stellated cells to explore the inhibition mechanisms and therapeutic potential of J-1048 as an ALK5 inhibitor in liver fibrosis. Our data showed that J-1048 inhibited TAA-induced liver fibrosis in mice by explicitly blocking the TGF-ß/Smad signaling pathway. Additionally, J-1048 inhibited the production of inflammatory cytokine Interleukin-1ß (IL-1ß) by inhibiting the purinergic ligand-gated ion channel 7 receptor (P2X7r) -Nucleotide-binding domain-(NOD-)like receptor protein 3 (NLRP3) axis, thereby alleviating liver fibrosis. Our findings demonstrated that a novel small molecule ALK5 inhibitor, J-1048, exhibited strong potential as a clinical therapeutic candidate for liver fibrosis.

Tolcapone Derivative (Tol-D) Inhibits Aß42 Fibrillogenesis and Ameliorates Aß42-Induced Cytotoxicity and Cognitive Impairment.

Abnormal aggregation and subsequent fibrillogenesis of amyloid-ß protein (Aß) can cause Alzheimer's disease (AD). Thus, the discovery of effective drugs that inhibit Aß fibrillogenesis in the brain is important for the treatment of AD. Our previous study has proven that tolcapone inhibits Aß fibrillogenesis and alleviates its cytotoxicity based on systematic in vitro and in vivo experiments. However, the severe hepatotoxicity of tolcapone seriously limits its further potential application in the treatment of AD. Herein, an inhibitory effect of a low-toxicity tolcapone derivative (Tol-D) on Aß fibrillogenesis was explored. Based on the thioflavin T fluorescence data, Tol-D inhibited Aß fibrillogenesis, and the inhibitory capacity increased with the increase of its concentrations with an IC50 of ∼8.99 µM. The results of cytotoxicity showed that Tol-D greatly reduced the cytotoxicity induced by Aß42 fibrillogenesis. Moreover, Tol-D significantly alleviated Aß deposits and extended the lifespan of nematodes in transgenic Caenorhabditis elegans models. Finally, Tol-D significantly relieved Aß-induced cognitive dysfunction in mice experiments. Overall, the above experimental results indicated that Tol-D is a novel candidate therapeutic compound for the treatment of AD.

Light-Mediated Signaling and Metabolic Changes Coordinate Stomatal Opening and Closure.

Stomata are valves on the leaf surface controlling carbon dioxide (CO2) influx for photosynthesis and water loss by transpiration. Thus, plants have to evolve elaborate mechanisms controlling stomatal aperture to allow efficient photosynthesis while avoid excessive water loss. Light is not only the energy source for photosynthesis but also an important signal regulating stomatal movement during dark-to-light transition. Our knowledge concerning blue and red light signaling and light-induced metabolite changes that contribute to stomatal opening are accumulating. This review summarizes recent advances on the signaling components that lie between the perception of blue/red light and activation of the PM H+-ATPases, and on the negative regulation of stomatal opening by red light-activated phyB signaling and ultraviolet (UV-B and UV-A) irradiation. Besides, light-regulated guard cell (GC)-specific metabolic levels, mesophyll-derived sucrose, and CO2 concentration within GCs also play dual roles in stomatal opening. Thus, light-induced stomatal opening is tightly accompanied by brake mechanisms, allowing plants to coordinate carbon gain and water loss. Knowledge on the mechanisms regulating the trade-off between stomatal opening and closure may have potential applications toward generating superior crops with improved water use efficiency (CO2 gain vs. water loss).

Preparation of 5-fluorouracil-loaded chitosan nanoparticles and study of the sustained release in vitro and in vivo.

The sustained-release properties of the biodegradable nano-drug delivery systems were used to improve the residence time of the chemotherapeutic agent in the body. These drug delivery systems were widely used to deliver chemotherapeutic drugs. The 5-fluorouracil loaded chitosan nanoparticles prepared in this paper have the above advantage. Here, we found that when the mass ratio of 5-fluorouracil and chitosan was 1:1, the maximum drug loading of nanoparticles was 20.13 ± 0.007%, the encapsulation efficiency was 44.28 ± 1.69%, the particle size was 283.9 ± 5.25 nm and the zeta potential was 45.3 ± 3.23 mV. The prepared nanoparticles had both burst-release and sustained-release phases in vitro release studies. In addition, the inhibitory effect of the prepared nanoparticles on gastric cancer SGC-7901 cells was similar to that of 5-fluorouracil injection, and the blank vector had no obvious inhibitory effect on SGC-7901 cells. In the pharmacokinetic study of rats in vivo, we found that AUC (0-t), MRT (0-t) and t 1/2z of nanoparticles were significantly increased in vivo compared with 5-fluorouracil solution, indicating that the prepared nanoparticles can play a role in sustained-release.