Latest ArticlesChitin is an abundant aminopolysaccharide found in insect pests and phytopathogenic microorganisms but absent in higher plants and vertebrates. It is crucial for mitigating threats posed by chitin-containing organisms to human health, food safety, and agriculture. Therefore, targeting the chitin biosynthesis-associated bioprocess holds a promise for developing human-safe and eco-friendly antifungal agents or pesticides. Chitin biosynthesis requires chitin synthase and associated factors, which are involved in the modification, regulation, organization or turnover of chitin during its biosynthesis. A number of enzymes such as chitinases, hexosaminidases, chitin deacetylases are closely related and therefore are promising targets for designing novel agrochemicals that target at chitin biosynthesis. This review summarizes the advances in understanding chitin biology over the past decade by our research group and collaborates, specifically regarding essential proteins linked to chitin biosynthesis that can be exploited as promising pesticide targets. Examples of small bioactive molecules that against the activity of these targets are given.
Prostaglandin E2 (PGE2) serves as the ultimate mediator of fever induced by inflammatory factors. In contrast to cyclooxygenase inhibitors that suppress arachidonic acid metabolism, antipyretic herbs possess a well-established clinical history in effectively managing fever. However, the specific mechanisms underlying their efficacy remain unclear. Following the screening for lead compounds that inhibit PGE2 from antipyretic herbs, alkynylated active molecule probes were designed and synthesized to track and identify potential targets. The target investigation revealed that three antipyretic compounds, namely cinnamaldehyde, 2,4-decadienal, and perillaldehyde, containing α,β-unsaturated aldehyde groups irreversibly targeted the microsomal PGES1-TM4 helix (mPGES1-TM4) at Ser139. This specific interaction effectually inhibited PGE2 production in the cerebral vasculature, leading to exert potent antipyretic effects. α,β-Unsaturated aldehydes targeting mPGES1-TM4 offer a new approach for antipyretic effects with significant potential for various applications.
Acute lung injury (ALI) is a critical respiratory disorder with a high mortality rate and is caused by several factors. Addressing oxidative stress and inflammation is a pivotal strategy for ALI treatment. In this study, we introduced a novel nanotherapeutic approach involving a curcumin-loaded ceria nanoenzyme delivery system tailored to counteract the multifaceted aspects of ALI. This system leverages the individual and combined effects of the components to provide a comprehensive therapeutic solution. The dual-action capability of this nanosystem was manifested by mitigating mitochondrial oxidative stress in lung epithelial cells and inhibiting the transient receptor potential melanosome-associated protein 2 (TRPM2)-NOD-like receptor thermal protein domain associated protein 3 (NLRP3) signaling pathway, offering a highly effective therapeutic approach to ALI. Our findings reveal the underlying mechanisms of this innovative nanodelivery system, showcasing its potential as a versatile strategy for ALI treatment and encouraging further exploration of nanoenzyme-based therapies for ALI.
Diabetes mellitus (DM) is a serious health problem in the world, and infections are common complications in diabetic patients, particularly methicillin-resistant Staphylococcus aureus (MRSA) infections, which substantially increases mortality in patients. In clinical practice, the treatment of diabetic complication-related infections involves multiple issues such as drug resistance when combining antidiabetic drugs with antibiotics. In this study, a series of derivatives were synthesized with alkyl radicals with different chain lengths substituted at the C8 and C12 positions of berberine, with compounds CY1 and CY3 with good antidiabetic and antibacterial activities screened out after identification. Then, oral liposomes (CY1-Lip and CY3-Lip) were prepared, and their particle sizes, stability, and pharmacokinetics were investigated. In acquired mouse models of diabetes, induced with an acute MRSA lung infection, we demonstrate that CY1-Lip and CY3-Lip can effectively reduce levels of fasting blood glucose (FBG), fasting insulin (FINS), and insulin resistance index among diabetic mice with pneumonia, thus exerting their multi-targets effects. Furthermore, both preparations significantly reduced lung MRSA loads and improved lung tissue lesions, reduced high infiltration of M1 macrophages in lung, and suppressed the expression levels of pro-inflammatory factors such as necrosis factor-α (TNF-α) and interleukin-6 (IL-6). This provides new insights into the clinical treatment of diabetes complicated with pulmonary infections.
Photoinitiators (PIs), as the key substances for photopolymerized antibacterial film (PAF), affect the cure rate and color of PAF. Herein, two enone dyes were designed and synthesized by a facile approach. Among the candidates, BDO1 has demonstrated the ability to initiate polymerization of acrylate monomers as single-component PI with the advantages of low mobility, outstanding photobleaching, excellent cytocompatibility, and suitability for light emitting diode (LED) light sources above 365 nm. Taking BDOs as examples, a novel method based on theoretical calculations aiming to assess the potential of enone molecules as single-component PIs was proposed. Finally, under the initiation of BDO1, tannic acid was photopolymerized to a colorless and transparent antibacterial film with high antibacterial ability, which indicated that BDO1 was expected to be used in environmentally friendly PAF.
Established evidence has unveiled two strategies for treating cancer: depleting tumor-associated macrophages (TAMs) and reprogramming M2-like TAMs into an antitumor M1 phenotype. Here, we designed novel pH-sensitive biomimetic hybrid nanovesicles (EDHPA) loaded with doxorubicin (DOX). DOX@EDHPA can specifically target TAMs by activating macrophage-derived exosomes (M1-Exos) and anisamide (AA) as cancer-specific targeting ligands. In vitro and in vivo studies demonstrated that DOX@EDHPA could efficiently be delivered to the tumor site and taken up by cells. Meanwhile, it synergistically enhanced immunogenic cell death (ICD) and induced a subsequent antigen-specific T cell immune response. The tumor inhibitory rate of the DOX@EDHPA group was 1.42 times that of the free DOX group. Further analysis showed that the excellent antitumor effects of DOX@EDHPA should ascribe to the homing effect of M1-Exos on macrophages and the repolarization to antitumor M1 TAMs, which induced the elevated secretion of pro-inflammatory factors. Therefore, the hybrid EDHPA targeting TAMs to reshape the tumor microenvironment constituted a novel immunochemotherapy strategy to inhibit tumor growth.
The occurrence, development, and metastasis of tumors often entail abnormal expression of genetic substances. Monitoring and regulating changes in intracellular nucleic acid substances hold promise for achieving accurate tumor diagnosis and effective treatment. However, the effectiveness of integrated tumor diagnosis and treatment based on functional nucleic acids still needs to be improved. In this study, we engineered a multifunctional nucleic acid delivery system grounded in a cationic covalent organic framework carrier. This system not only showcases effective gene silencing but also boasts high sensitivity in detecting miR21 levels within tumor cells, enabling real-time monitoring of tumor gene therapy efficacy. The construction of this integrated functional nucleic acid delivery platform provides new ideas for precise tumor detection and effective tumor treatment.
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with high mortality rate but effective therapeutics are still lacking. Phosphodiesterase-4 (PDE4) inhibitors were reported to be promising anti-IPF agents. Herein, series of biflavonoids isolated from Selaginella uncinate were found to be PDE4 inhibitors and the most active amentoflavone gave a half maximal inhibitory concentration (IC50) of 12 nmol/L, which was further validated by isothermal titration calorimetry with Kd of 23 nmol/L. Besides, co-crystal structure of PDE4-amentoflavone was determined and gave a different binding pattern from roflumilast with multiple H-bonds between it and key residues such as Asn321/Thr333/Gln369/Gly371. So far, this was the first reported co-crystal structure of amentoflavone with its potential binding target in despite of the extensive investigations of this common natural biflavonoid. Furthermore, amentoflavone exhibited remarkable anti-IPF effects in vivo and in vitro, suggesting it as a novel anti-fibrotic agent by targeting PDE4.
Recently, MP-10, a previous drug candidate with potent inhibition of phosphodiesterase 10A (PDE10A) in clinical phase II trials for schizophrenia or Alzheimer's disease, has shown significant potential in preventing and treating cardiovascular diseases. However, its poor metabolic stability and high permeability across the blood-brain barrier (BBB) make it unsuitable for preventing and treating peripheral cardiovascular diseases. Herein, the hit-to-lead optimization was performed to discover novel 3-trifluoromethyl-substituted pyrazole derivatives as potent and selective PDE10A inhibitors. The structure-activity relationships, biological characterization, molecular mechanism, and drug-like evaluation were discussed to identify compound C7 which showed potent inhibition against PDE10A (half maximal inhibitory concentration, IC50 = 11.9 nmol/L), more than 840-fold selectivity over other PDE subtypes, enhanced liver microsomes stability (T1/2 = 239 min) compared to MP-10 and low BBB permeability. Importantly, oral pretreatment with C7·3HCl at a dose of 5.0 mg/kg significantly attenuated the pathological and functional changes induced by isoprenaline (ISO)-induced pathological cardiac hypertrophy in mice, particularly suppressing increase of cardiac weight, atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MHC) hypertrophic markers along with cardiac fibrosis. These findings further support that targeting PDE10A provides an innovative therapeutic approach for preventing and treating cardiac diseases.
In this work, we put forward a new and universal approach, i.e., cyanine ketone method, for fabricating meso–aryl heptamethine indocyanines, which is so simple that the treatment of the easy-to-get cyanine ketones with various aromatic lithium (ArLi), followed by acidification, could straightforwardly give rise to the products in one-pot way. Importantly, due to the strong nucleophilicity of ArLi, a series of bulky hydrophilic aromatic groups can be facilely integrated into the meso–position of heptamethine indocyanines, not only effectively inhibiting the undesired dye self-aggregation but also largely improving the water-solubility. Using one of anti-aggregation meso–aryl heptamethine indocyanines, we fabricated a dye-antibody conjugate for in vivo imaging tumor in a mouse model and achieved a high tumor-to-normal tissue ratio. The work laid a chemical foundation for constructing various meso–aryl heptamethine indocyanines, facilitating the advanced imaging and therapeutic applications in future.
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